B. M. Pettitt's Publications

SCF-LCAO-MO calcns. were made for NeHHe+. The complex has a min. energy of -131.49544 hartree, corresponding to He-H and Ne-H bond distances of 1.875 and 2.05 bohr, resp. The reactions NeH+ + He -> NeHHe+ and Ne + HHe+ -> NeHHe+ are exothermic by 9.4 and 14.5 kcal/mol, resp. [on SciFinder (R)]

Keywords: Heat of reaction (of helium-group gas hydride ion); Potential energy and function (surface of, for helium hydride ion collinear reaction with neon) MO hydride neon helium; potential surface hydride helium neon; heat reaction helium neon hydride; energy potential helium neon hydride

The total Compton profiles and anisotropies assocd. with momentum distribution along vectors parallel and perpendicular to bond axes in alkali chloride mols. are calcd. and related to changes in charge distributions accompanying bond formation. [on SciFinder (R)]

Keywords: Alkali metal chlorides Role: PRP (Properties) (Compton profile anisotropy of, MO calcn. of); Bond formation (alkali metal-chlorine, Compton profile anisotropy in relation to); Molecular orbital (ab initio SCF, Compton profile anisotropy of alkali metal chlorides); Compton effect (profiles, of alkali chlorides, charge distribution in relation to, MO calcn. of) alkali chloride Compton profile anisotropy

Anisotropies assocd. with momentum distributions along vectors parallel and perpendicular to bond axes in alkali metal bromide mols. are computed and analyzed. An attempt is made to relate these to charge cloud deformations accompanying mol. formation. The parallel profile assocd. with the valence p orbital is the dominating factor detg. the relative shapes of the total profile anisotropies in the low momenta regions Pz ? 0.5. [on SciFinder (R)]

Keywords: Alkali metal bromides Role: PRP (Properties) (Compton profile anisotropy in); Compton effect (profiles, anisotropy of, in alkali metal bromide) Compton profile lithium sodium bromide

An empirical relation between zero point Compton profile anisotropies DJ(0) and nuclear charges is noted. To a good approxn., DJ(0) = Nln(Zb/Za) for alkali halide mols., AB. [on SciFinder (R)]

Keywords: Molecules (Compton profile anisotropies in); Alkali metal halides Role: PRP (Properties) (Compton profile anisotropies in); Nuclear charge (Compton profile anisotropies in relation to); Compton effect (in mols. and in solids, anisotropies of) Compton profile mol solid; nuclear charge Compton profile; alkali halide Compton profile

Calcns. of Compton profiles and parallel-perpendicular anisotropies in alkali fluorides are presented and analyzed in terms of mol. charge distributions and wave function character. The parallel profile assocd. with the valence p orbital is the principal factor detg. the relative shapes of the total profile anisotropies in the low momentum region. [on SciFinder (R)]

Keywords: Electron configuration; Wave function (Compton profile anisotropies in alkali metal fluorides in relation to); Alkali metal fluorides Role: PRP (Properties) (Compton profile anisotropies in, electron configuration in relation to); Compton effect (anisotropies of, in alkali metal fluorides, electron configuration in relation to); Electron configuration (p-, Compton profile anisotropies in alkali metal fluorides in relation to) Compton profile alkali metal fluoride

SCF-LCAO calcns. were done to obtain: (a) the optimized DIM potential-energy (PE) surface for the reaction of ArH+ and He; (b) the parameters of the Morse PE curves of ArH+, ArH, HeH+, HeH, HeAr+, and HeAr; and (c) the frequencies of the sym. and asym. stretching vibrations of 40ArHHe+, 40ArDHe+ 36ArHHe+, and 36ArDHe+. For (ArHHe)+ at the PE min., the energy is -529.7778 hartree, and the Ar-H and H-He interat. distances are 2.51 and 2.82 bohr, resp. The energies for the exothermic reactions ArH+ + He -> ArHHe+, Ar + HHe+ -> ArHHe+, and Ar + HeH+ -> ArH+ + He are 1.58, 41.4, and 39.8 kcal/mol, resp. [on SciFinder (R)]

Keywords: Heat of reaction (of argon and hydrohelium(1+), SCF-LCAO calcns. of); Molecular vibration (of argon-helium-hydrogen and argon-deuterium-helium triat. monopos. ions, SCF-LCAO calcns. of); Potential energy and function (Morse, for diat. mols. and monopos. ions from argon and helium and hydrogen, SCF-LCAO calcns. of); Potential energy and function (surface, for helium-hydroargon(1+) reaction, SCF-LCAO calcns. of) potential surface helium hydroargon cation; reaction helium hydroargon cation SCF; heat reaction argon hydrohelium cation; vibration triatomic argon helium hydrogen; Morse potential argon helium hydrogen; hydride argon helium Morse potential; deuterium argon helium triatomic vibration; hydrogen argon helium triatomic vibration

A correlation between bond polarities and zero point Compton profile anisotropies is shown for alkali halide mols. The correlation derives from the fact that both quantities are detd. by mol. binding and antibonding forces and are thus functionally related to nuclear charge ratios. [on SciFinder (R)]

Keywords: Compton effect (bond polarity in alk. metal halide in relation to); Alkali metal halides Role: PRP (Properties) (polarity and Compton profile anisotropy in); Bond (polarity of, in alk. metal halides, Compton profile anisotropy in relation to) Compton effect bond polarity halide; alkali halide Compton bond polarity

A classical derivation of a dipole moment model derived earlier (M. and K. 1976, 77) by a quantum mech. implicit perturbation technique is given. This model is used to det. the bond polarities of the posttransition (Groups IIIA-VIIA) hydrides. The polarity measures the extent of charge transfer in a bond. Polarities of alkali halides and posttransition hydrides are used to illustrate the gradual change in bond polarities with nuclear charge across the periodic table. [on SciFinder (R)]

Keywords: Nuclear charge (bond polarity in hydrides in relation to); Alkali metal halides; Hydrogen halides Role: PRP (Properties) (bond polarity of); Bond (polarity of, of posttransition metal hydrides); Electric charge (transfer of, in posttransition metal hydride bond, polarity in relation to); Group IIIA element compounds; Group IVA element compounds; Group VA element compounds; Group VIA element compounds Role: PRP (Properties) (hydrides, bond polarity of); Hydrides (posttransition, bond polarity of) bond polarity posttransition hydride; IIIA hydride bond polarity; IVA hydride bond polarity; VA hydride bond polarity; VIA hydride bond polarity; VIIA hydride bond polarity; hydrogen halide bond polarity; alkali halide bond polarity

A procedure, based on Rayleigh-Schroedinger perturbation theory, for obtaining vibrational, rotational, and temp.-dependent Compton profiles and profile anisotropies is presented and applied to H2 to test its validity. The computer vibrational-rotational dependence agrees well with the results of V. H. Smith et al. (1977) who obtained vibrational-rotational profiles for H2 by numerically integrating the Schroedinger equation for nuclear motion. The procedure is used to obtain vibrational, rotational, and temp.-dependent profiles and anisotropies for some alkali halide mols. The vibrational and temp. dependence of the parallel-perpendicular anisotropies in these mols. is substantial. [on SciFinder (R)]

Keywords: Alkali metal halides Role: PRP (Properties) (Compton profile anisotropies in, rotational, temp., and vibrational dependence of); Molecular rotation; Molecular vibration (alkali metal halide Compton profile anisotropy dependence on); Compton effect (profiles, for alkali metal halides, anisotropies of) alkali halide Compton profile anisotropy

A generalization of the RISM (ref. interaction site model) integral equation for site-site pair correlation functions previously proposed by the authors is discussed and applied to model liqs. composed of strongly polar diat. mols. The nonuniform mol. charge distribution is represented by the introduction of charged interaction sites. The generalization consists of applying closure conditions analogous to those which are known to be reasonable for the description of at. ionic fluids, and the corresponding renormalization of the contributions arising from long range forces. The symmetry properties of the pair correlation functions in special cases and the dielec. properties implied by theory are discussed. Applications are presented for three two-site models which differ substantially in the degree of asymmetry of the non-Coulombic potential between the two sites, and for three-site models for Br2. The two sites models are compared to computer simulation results, and those for Br2 to exptl. results. The integral equation is well balanced in that in every case the qual. features of the liqs. structure which are introduced by polarity are well represented, even in cases where the site-site potentials are individually much larger than kBT. In cases where the mol. shape and polar forces are in competition, the results are of comparable accuracy to the corresponding theory for nonpolar systems. In the extreme case where changes in orientational structure can occur without interfering with packing requirements, the results appear quant. less reliable. [on SciFinder (R)]

Keywords: Dielectric property (of dipolar and quadrupolar fluids, ref. interaction site model in); Statistical mechanics (ref. interaction site model, of dipolar and quadrupolar fluids); Distribution function (pair correlation, site-site, of dipolar and quadrupolar fluids) statistical mechanics quadrupolar fluid; correlation function quadrupolar fluid; dielec property quadrupolar fluid

An application of the authors recently developed extended RISM equation formulation (1981) to several 3-site models of H2O is presented. The site-site correlation functions are obtained and compared to available computer simulation results. Further, the variation of liq. state structure with the model site charge is examd. The anal. of these results has demonstrated that the integral equation approach provides a correct qual. description of the liq. structure, although the amplitudes of most structural features are somewhat less accurate than their positions. Comparison to earlier results for simpler models suggests that the nature of the quant. deficiencies of the approach is predictable. The charging study has shown that the development of waterlike structure with increasing site charge follows a qual. different pattern for O-O pairs, compared to those involving hydrogen. This is attributed to interference between the amplitudes characteristic of liq. water and of simple liqs. This is the origin of a relatively flat 0-0 correlation function for several models studied in the past, and, further, that such results should not be properly characterized as ünstructured. [on SciFinder (R)]

Keywords: Liquid structure (waterlike intermol. potentials in); Potential energy and function (intermol., liq. structure in relation to) liq structure potential; water liq structure

The generalization of a recently proposed extension of the RISM (ref. interaction site model) integral equation to infinitely dil. isolated ions and ion pairs in polar interaction site model mol. solvents is outlined. An essential element of the development is the explicit sepn. of the contributions which yield a continuum dielec. solvent model from the remainder. Thus, it is only for this correction that one relies on the integral equation. Application is made to a system consisting of a diat. polar solvent and at. ions of varied charge and radius. The results of the calcns. show that this approach produces qual. features of ionic solvation including an appropriately varying degree of solvent orientational satn. with ionic charge and radius. Correspondingly, the calcd. interionic potentials of mean force reproduce the same basic features manifest in already available studies of dipolar hard sphere solvents, including the positions of oscillatory features in the structure and the relatively short spatial range of the corrections to the continuum dielec. theory. [on SciFinder (R)]

Keywords: Solutes (in polar solvents, interionic potential in relation to); Liquid structure (interionic potential of mean force in mol. polar solvent in relation to); Ion pairs; Ions in liquids (interionic potential of, in mol. polar solvent); Solvation (ionic, interionic potential of mean force in mol. polar solvents in relation to); Electric charge (of ions in polar solvents, interionic potential of mean force in relation to); Dielectric constant and dispersion (of polar solvent, interionic potential of mean force in relation to); Potential energy and function (interionic, of mean force in mol. polar solvent from extended from IRSM equation); Solvents (polar, mol., interionic potential of mean force in) interionic potential mean force solvent; RISM polar solvent interionic potential

The structure of liq. MeOH was studied using the recently proposed extended RISM integral equation and Jorgensen's transferable intermol. potentials (TIPS). Results are obtained as a function of mol. polarity by scaling the partial Coulombic charges located at mol. interaction sites. At the exptl. d., packing forces are predominant in detg. many features of the liq. structure, as reflected in site-site correlation functions. The influence of H bonding is best characterized as a narrowing in the mol. distributions, resulting from an accommodation of the attractive forces within structural alternatives consistent with packing constraints. [on SciFinder (R)]

Keywords: Hydrogen bond (in liq. methanol, structure in relation to); Liquid structure (of methanol, hydrogen bonding in relation to); Distribution function (radial, site-site, in liq. methanol) methanol liq hydrogen bond structure

The parallel-perpendicular Compton-profile anisotropies were calcd. for the 1st-row diat. hydrides. Both the total and MO anisotropies present trends that were related to the nature of the chem. binding in the mols. [on SciFinder (R)]

Keywords: Bond (in diat. hydrides of 1st row, Compton profiles in relation to); Compton effect (profiles, of diat. hydrides of 1st row, bonding in relation to); Hydrides Role: PRP (Properties) (diat., Compton profiles of 1st-row, bonding in relation to) beryllium hydride Compton profile bonding; lithium hydride Compton profile bonding; diatomic hydride Compton profile bonding; hydrogen fluoride Compton profile bonding; imidogen Compton profile bonding; methylidyne Compton profile bonding; hydroxyl Compton profile bonding; borane Compton profile bonding

A simple modification of the HNC-like closure within the extended RISM equation formalism is considered which ensures that the asymptotic form of the site-site direct correlation functions is consistent with the dielec. const. The short ranged structural results obtained with the modification are compared with those following from the original closure for 3 strongly polar diat. models, and show very small differences. These results demonstrate both that the short ranged results are only weakly coupled to the asymptotic amplitudes, and that the latter can potentially be cor. in a relatively straighforward manner. [on SciFinder (R)]

Keywords: Dielectric constant and dispersion (of mol. liqs., extended interaction site models for correlation functions in relation to); Distribution function (correlation, of mol. liqs., extended interaction site models for, dielec. const. in relation to) interaction site model liq correlation; dielec const liq correlation function

The contribution of electrostatic interactions to a range of structural, energetic, and dynamic properties of the alanine dipeptide is examd. An empirical energy function is employed to represent the dipeptide, and the partial at. charges are varied from zero to values used in std. models for amino acids and proteins. Although there are large differences in the abs. energy of models with different charges, the relative energies of the various dipeptide conformers are less sensitive to the charges. The min. energy structures of the conformers are only weakly dependent on the charges. A normal model anal. shows that only a few modes are sensitive to the charges and that thermodn. quantities, which represent sums over the modes, are essentially the same for all the models. Comparison of the harmonic dynamics results with those from an ensemble of mol. dynamics trajectories reveals that the electrostatic contributions to the potential surface introduce significant anharmonic effects. [on SciFinder (R)]

Keywords: Enthalpy and Enthalpy function; Entropy; Free energy (harmonic, of alanine dipeptide); Hydrogen bond (in alanine dipeptide, electrostatic contribution in relation to); Heat capacity; Molecular dynamics; Molecular vibration (of alanine dipeptide); Molecular structure (of alanine dipeptide, electrostatic contribution in); Conformation and Conformers (of alanine dipeptide, electrostatic contribution in relation to); Potential energy and function; Potential energy surface and hypersurface (of alanine dipeptide, electrostatic contribution to); Peptides Role: PRP (Properties) (di-, alanine-contg., electrostatic interaction in, calcn. of) alanine dipeptide electrostatic interaction; methylalanylacetamide electrostatic interaction; structure alanine dipeptide electrostatic interaction; mol dynamics alanine dipeptide; energy alanine dipeptide electrostatic interaction; thermodn alanine dipeptide electrostatic interaction; conformation alanine dipeptide electrostatic interaction

An exact form for the time dependent resonance Raman kernel at finite temperature is derived under the assumption that the ground and excited state potential surfaces of the system are harmonic. The resultant expression can be evaluated by matrix algebra and Fourier transformed numerically to recover Raman scattering and excitation profiles.

Keywords: Raman Spectroscopy; Line Shape; Resonance Scattering; Temperature Dependence

Theoretical results obtained with the extended reference interaction site (XRISM) formalism are presented for site–site solute solvent correlations and solute–solute potentials of mean force for infinitely dilute polar molecular solutes in various polar solvents. The standard RISM site–site Ornstein–Zernike like equations, in a Coulomb renormalized form, with a hypernetted chain (HNC) analog closure are used to derive results for polar molecular solutes in polar molecular solvents. For a dipolar diatomic solute the difference in the solvation behavior between atomic and molecular solvents is examined. Finite concentration results are compared with the infinite dilution intermolecular site–site potentials of mean force for diatomic molecules in a simple fluid solvent.

Keywords: Polyatomic Molecules; Solutions; Correlations; Intermolecular Forces; Liquid Structure

The results of an application of integral equation theory to the detn. of the intramol. potential of mean force for the alanine dipeptide, N-methylalanine acetamide, in aq. soln. are presented. The calcns. are based on Ornstein-Zernike-like equations for polar systems with an intramol. superposition approxn. The solvated free energy surface for the dipeptide as a function of the dihedral angles f and y (Ramachandran plot) is detd. and compared with the vacuum surface calcns. Conformations that are essentially forbidden in vacuum are found to be significant in aq. soln. The solvent contributions to the free energy surface are decompd. into enthalpic and entropic terms. Possible applications and extensions of the method are outlined. [on SciFinder (R)]

Keywords: Conformation and Conformers (of methylalanine acetamide, potential energy surface calcns. in relation to); Potential energy surface and hypersurface (conformational, of methylalanine acetamide) methylalanine acetamide potential energy surface conformation; alanine dipeptide potential energy surface conformation

The effects of Coulomb potential truncation schemes used in computer simulations of ionic and polar fluids are examined by use of integral equation techniques. A renormalized HNC type equation capable of describing both ionic and polar molecular fluids with truncated interactions is derived and applied to several model systems of interest. Good agreement is found between the integral equation results and Monte Carlo simulations of the same potential for dilute solutions of ions in a dielectric continuum. Very large effects on the distribution functions result from truncation of the electrostatic interaction in dilute systems. Even in comparatively dense systems, unrealistic pair correlations near the cutoff distance result from some of the proposed truncation schemes. The effect of Coulomb potential truncation for a molecular model of pure water is also studied. Significant errors appear in the second neighbor region for commonly used truncation schemes; a simple switching function that zeros the potential and its first derivative yields results closest to the Coulomb potential without truncation.

Keywords: Computerized Simulation; Potentials; Liquids; Coulomb Field; Intermolecular Forces

By using the specialization of the extended RISM equation to infinitely dil. systems, correlation functions and interionic potentials of mean force were calcd. for a set of models corresponding to the first few alkali halides in water. From the results obtained at infinite diln., the lowest order corrections were calcd. to the soln. properties of the ions. Higher concns. are explored by using the interionic potentials. The results indicate that certain thermodn. properties, such as the mean activity coeffs. and osmotic pressures, are quite sensitive to the details of both the theory and the potential models. [on SciFinder (R)]

Keywords: Alkali metal halides Role: PRP (Properties) (interionic potentials for, in aq. solns.); Activity; Osmotic pressure (ion-solvent correlations and ion-ion potentials of means force at infinite diln. in relation to); Distribution function (correlation, of alkali halides in water); Potential energy and function (interionic, of alkali halides in water) alkali halide aq ion solvent correlation; potential infinite diln alkali halide aq

A review with 80 refs. Energy of interaction between drugs and receptors is discussed in terms of drug design. [on SciFinder (R)]

Keywords: Receptors Role: BIOL (Biological study) (drug interaction energies with, drug design in relation to) review drug design interaction energy

A model is presented for detg. the intramol. potential of mean force for flexible polyat. mols. in aq. soln. This is an essential step in developing a reduced simulation technique for studying solvated biopolymers. The Ornstein-Zernike integral equation theory within a superposition formalism led to a convenient and efficient method for calcg. the solvent-modified intramol. potential. Solute-solvent distribution functions for the atoms (sites) composing the polyat. mol. are evaluated individually and introduced into the appropriate integral equations to obtain the site-site potentials of mean force for all distinct atom pairs in the mol. The superposition approxn. plus an empirical energy function for the internal degrees of freedom can then be employed to det. the total solvent-modified potential of mean force surface for the mol. system. An application to the evaluation of the intramol. potential of mean force surface for the alanine dipeptide (N-methylalanylacetamide) under vacuum and in aq. soln. is given to illustrate the method. [on SciFinder (R)]

Keywords: Statistical mechanics (Ornstein-Zernike-type integral equation, solvent-modified potential surface for flexible internal degrees of freedom of biomols. construction by); Solvation (of biomols., potential surface for); Potential energy surface and hypersurface (solvent-modified, for flexible internal degrees of freedom of bimols.); Biopolymers; Peptides Role: ANST (Analytical study) (solvent-modified, potential surface for) biomol solvation potential surface calcn; statistical mechanics potential surface peptide

Recently developed integral equation methods for the evaluation of intermol. and intramol. interactions in a polar solvent medium are discussed and representative applications are presented. Examples include solvent modification of interionic interactions between at. or mol. ions in water and liq. environment induced shifts in conformational equil. for both non-polar and polar flexible mols. in water. Emphasis is placed on the features of these phenomena which can be traced specifically to the molecularity of the solvent and hence cannot be adequately reproduced by a simple continuum dielec. solvent representation. 49 Refs. [on SciFinder (R)]

Keywords: Solvent effect (on mol. interactions); Potential energy and function (solvent effects on) review solvent mediated mol interaction

Calcns. of the site-site correlation functions for a model of water were performed as functions of d. or pressure at fixed temp. These calcns. are discussed and compared to neutron-scattering data. They structure of liq. water at high pressure is consistent with a substantially distorted H-bonding network. Unlike MeOH, water cannot easily accommodate structures assocd. with directional attractive forces in the region of several kilobars of pressure. [on SciFinder (R)]

Keywords: Hydrogen bond (in water at high pressure); Liquid structure (of high-d. water); Distribution function (correlation, of water, at high pressure) water structure correlation function; hydrogen bond water

Recently developed integral equation methods for the evaluation of correlations of polar mol. solutes in polar solvent media have been solved for the N-Me alanyl acetamide in H2O. The results are compared with simulations of similar model systems. The use of the full mol. site-site correlations detd. in this work can be used in approx. nonsuperposition theories for conformational populations in soln. [on SciFinder (R)]

Keywords: Hydration (of peptides, model for); Peptides Role: BIOL (Biological study) (structure of water around, calcn. of); Hydrogen bond (water structure surrounding peptides response to, modeling of) peptide water structure model; methylalanyl acetamide water structure model

An inhomogeneous anisotropic integral equation theory is used to predict the 6-fold pattern of intensity in the structure factor for graphite intercalation compds. The competition of length scales implied by particle size and the underlying lattice through the interplay of the liq. packing structure with the graphitic external field is shown to be responsible for the obsd. halo-like features in S(k). By using a d. functional motivated ansatz no explicit truncation of the angular Fourier components of the d. distributions was necessary. [on SciFinder (R)]

Keywords: Alkali metals Role: PRP (Properties) (structure factor of graphite intercalation compds. contg.); Potential energy and function (periodic, two-dimensional fluids in); Distribution function (structure factor, of graphite intercalation compds.) structure factor graphite intercalation compd

Preliminary results are reported for dynamic computer free energy simulations for a pair of Cl-, ions in H2O with a near-ion-contact starting configuration. A contact min. is obsd. in which the 2 ions are able to oscillate for some time. Water mols. form bridging H bonds which stabilize the ion pair. [on SciFinder (R)]

Keywords: Ion pairs (chloride-chloride, at contact, simulation of) ion pair chloride chloride solvated; computer simulation chloride ion pair; contact chloride chloride ion pair

An effective intramol. potential is presented for use in conjunction with existing 3-site models of water. Two commonly used internal geometries were fit to the same form and yield slightly different parameterizations. By including a Urey-Bradley-like term in an otherwise std. mol. mechanics form, the exptl. transition frequencies of water monomer can be reproduced accurately. Good qual. agreements for spectral shifts were subsequently found for the models in condensed-phase applications. Harmonic anal. of clusters indicates good qual. agreement with exptl. environmental shifts in frequencies at low temps. for these models. This model should be useful for a wide variety of applications including simulations of biopolymers and ionic solns. [on SciFinder (R)]

Keywords: Potential energy and function (intramol., for water) intramol model potential water

A quant. study is reported of the Cl-Cl- solvent-averaged potential in water, detd. by using the ümbrellasampling method and the Hamiltonian used in a recent integral equation study. The resulting potential of mean force is compared to the result from previous approx. integral equation studies. The results display a clear contact stabilization in contrast to the predictions of continuum theory. [on SciFinder (R)]

Keywords: Potential energy and function (pair, solvent-averaged, between two chloride ions in water, quantum statistical mech. study of); Statistical mechanics (quantum, of chloride ion pairs in water) chloride ion pair water; potential interionic chloride water

The extended ref. interaction site method is used to calc. the structure of water behind a shock front. The competing effects of increased d. and temp. modify the correlation functions in a manner that is qual. consistent with both expectation and recent exptl. results. [on SciFinder (R)]

Keywords: Shock wave (in structure of water); Liquid structure (water, behind shock waves) water structure shock wave effect

Mol. dynamics computer simulations utilizing the thermodn. cycle-perturbation method were used in preliminary calcns. of the relative free energies of binding for 2 new compds. (I and II) with antiviral activity to the coat proteins of human rhinovirus 14. The results suggest that intrinsic protein-ligand interactions dictate relative binding affinities, whereas relative desolvation energies contribute little to the net differences in the free energy of binding. These results and similar calcns. currently in progress should contribute to the design of new mols. with enhanced binding affinity for the rhinovirus coat proteins. [on SciFinder (R)]

Keywords: Free energy (of binding, of phenoxyisoxazole to rhinovirus coat protein, by perturbation method); Solvation (of phenoxyisoxazole antiviral agents); Molecular association (of phenoxyisoxazole antiviral drugs, with rhinovirus coat proteins, thermodn. of); Process simulation (mol. dynamics, of phenoxyisoxazole antiviral agents); Virus (rhino-, coat proteins, phenoxyisoxazole inhibitors binding to, thermodn. of); Molecular structure-biological activity relationship (virucidal, of phenoxyisoxazoles) antiviral phenoxyisoxazole mol dynamics; thermodn solvation binding phenoxyisoxazole antiviral; free energy phenoxyisoxazole

Integral equation theory is applied to the detn. of the intramol. potential of mean force for the glycine peptide, N-acetylglycyl-N-methylamide, in aq. soln. The solvated free energy for the dipeptide as a function of the dihedral angles F and Y (Ramachandran plot) is detd. and compared with the vacuum surface. Conformations forbidden in vacuum are found to be populated in aq. soln. The results for the glycine dipeptide are compared to a parallel study on the alanine dipeptide. Solvent effects are responsible for the extent of many of glycine's properties related to flexibility. [on SciFinder (R)]

Keywords: Conformation and Conformers; Potential energy surface and hypersurface (of glycine dipeptide); Solvent effect (on conformation of glycine dipeptide); Potential energy and function (conformational, of glycine dipeptide) glycine dipeptide conformation

A method that locates transition state structures homologous reactions and, with the use of the thermodn. cycle-perturbation technique, dets. the relative free energy of activation between the transition states is presented. A simple model system which displays the problem of finding condensed phase transition states is used to illustrate the method. [on SciFinder (R)]

Keywords: Free energy of activation (between transition state structures of homologous reactions, geometric method for calcn. of); Transition state structure (location of, between homologous reactions, geometric method for detn. of) transition state structure free energy activation

Simulations of the residual configurational entropy of a protein in the native state suggest that it is nearly an order of magnitude larger than the entropy of denaturation. The implications of this result are discussed. [on SciFinder (R)]

Keywords: Proteins Role: PRP (Properties) (configurational entropy of, simulation of); Entropy (of denaturation, of proteins, configurational entropy in relation to); Entropy (configurational, of proteins, simulation of) protein configurational entropy

Keywords: Proteins Role: PRP (Properties) (dynamics and structure and thermodn. of); Thermodynamics (of proteins, dynamics and structure in relation to) protein dynamics structure thermodn book

A review with 38 refs. By appropriate choice of the level of theor. treatment, the problem of accounting for the soln. environment in the modeling of biopolymer conformation and interactions is becoming accessible to direct computational evaluation. In this article, the authors summarize a no. of methods that have been recently applied in this context, emphasizing those other than direct all-atom computer simulation. [on SciFinder (R)]

Keywords: Biopolymers Role: ANST (Analytical study) (conformation and interactions of, solvation effects in, modeling of); Solvation (in biopolymer solns., modeling of, conformation and interactions in relation to); Conformation and Conformers (of biopolymers, solvation effects in, modeling of); Process simulation (of solvation effects in biopolymer soln.) review solvation effect biopolymer; conformation biopolymer solvation effect review; process simulation biopolymer solvation review

We have performed a molecular dynamics simulation of the enkephalin derivative Tyr-(D)Pen-Gly-Phe-(D)Pen (DPDPE) in aqueous solvent. Electrostatic interactions were calculated with the Ewald method so as to accurately model the large interactions between the DPDPE zwitterion and the solvent and to avoid the use of electrostatic cutoff's or neutral chemical blocking groups. DPDPE is found to be extremely constrained with very little variation in the main-chain dihedral angles. Flexibility found in the region of the central glycine is greatly restricted compared with glycines in straight-chain peptides. Several conformational transitions are observed for the two aromatic side chains, indicating a high degree of flexibility in the side chains and that DPDPE does not have a single conformation in solution. This suggests that the arrangement of the tyrosine and phenylalanine aromatic residues in the bound conformation may be selected by the receptor environment. The main-chair conformation of DPDPE in solution has a parallel arrangement of peptide groups. This electrostatically unfavorable structure is stabilized by interactions of the carbonyls with the solvent. Solvent structure around the N terminus is found to be considerably localized, involving short ammonium cation to water contacts with lifetimes of the order of 50 ps or more. In comparison, water structure around the C terminus is much more mobile with lifetimes of the order of 20 ps or less.

A computational demonstration of a form of constant-chemical-potential molecular dynamics shows the feasibility of the proposed method. The technique is based on using a Lagrangian for a system that includes extension variables to couple the number of particles with the chemical potential and auxiliary variable allowing for the insertion of new particles and the destruction of existing ones. Density dependence, equilibrium and non-equilibrium properties are considered.

A review, with 23 refs., on a representative 150-ps mol. dynamics simulation of metmyoglobin in water, the general methods used in this dynamic simulation, and spatial and temporal fluctuations. [on SciFinder (R)]

Keywords: Myoglobins Role: PRP (Properties) (time scales and fluctuations of metmyoglobin dynamics in aq. soln.) review metmyoglobin dynamics soln

The aqueous solvation thermodynamics of cis- and trans-N-methylacetamide is studied by integral equation theories and molecular dynamics simulations and compared with Monte Carlo results (Jorgensen, W. L.; Gao, J. J. Am. Chem. Soc. 1988, 110, 4212). Although the hypernetted chain (HNC) approximation is generally recommended for polar systems, the solvation free energy derived from the Gaussian fluctuation (GF) approximation gives much better absolute solvation thermodynamics. With the same atomic charges for the two conformers, the difference in solvation free energy between the cis and trans conformers equals 1-2 kcal/mol from the HNC and GF approximations, in approximate agreement with the value of 2.2 kcal/mol from a Monte Carlo simulation with very similar parameters. The simpler superposition approximation introduced by Pettitt and Karplus (Chem. Phys. Lett. 1985, 121, 194) gives results for the relative solvation thermodynamics (cis versus trans conformers) that compare well with the more exact integral equation theories.

We present two techniques for implementing a new method of simulating an entire virion. Earlier computer simulations of a capsid protein revealed large edge effects due to the use of free standing boundaries. Because of the size of a given protomer, conventional three-dimensional periodic boundary conditions would be extremely wasteful. This would require an extremely large number of solvent molecules, and therefore would be computationally feasible for only a fragment of the entire virion. The new method employs non-space-filling computational cells in molecular modeling and molecular dynamics with the boundary conditions based on the icosahedral group. The method is general and could be used for any molecular system with a point group symmetry. With this method, the dynamical and spatial intra and interpromotomer correlations can be studied at atomic levels. The technique is applicable to any virion with icosahedral symmetry. A sample calculation involving a geometry optimization of the human rhinovirus coat proteins is given to demonstrate the technique.

Molecular dynamics simulations of a zwitterionic bis(penicillamine) enkephalin derivative in 1.0 M saline solution have been performed. Two simulations produced essentially the same average results although they differed in the initial random placement of the salt ions. The dynamical and structural properties from the simulations were compared with those from a previous simulation of the peptide in pure water. The properties of the sodium and chloride ions were compared with those from a simulation of bulk salt solution. An inner-sphere complex between the peptide and the chloride ions was observed in which two to three chloride ions were associated with the NH3+ terminal hydrogen atoms. Several chlorides associated with more than one amide hydrogen simultaneously, and the resulting close chloride-chloride ion contacts were additionally stabilized by bridging water molecules. The sodium ions did not associate directly with the peptide but formed an outer-sphere complex surrounding the peptide-chloride ion complex. The effect of chloride ion association on the structure and dynamics of the peptide was investigated in detail. The spatial correlations between salt ions and the enkephalin derivative are discussed in relation to delta-opioid receptor binding. The implications that the observed ion effects have on our understanding of the Hofmeister series are also considered.

A class of triplex-forming oligodeoxyribonucleotides (TFOs) is described that can bind to naturally occurring sites in duplex DNA at physiological pH in the presence of magnesium. The data are consistent with a structure in which the TFO binds in the major groove of double-stranded DNA to form a three-stranded complex that is superficially similar to previously described triplexes. The distinguishing features of this class of triplex are that TFO binding apparently involves the formation of hydrogen-bonded G.GC and T.AT triplets and the TFO is bound antiparallel with respect to the more purine-rich strand of the underlying duplex. Triplex formation is described for targets in the promoter regions of three different genes: the human c-myc and epidermal growth factor receptor genes and the mouse insulin receptor gene. All three sites are relatively GC rich and have a high percentage of purine residues on one strand. DNase I footprinting shows that individual TFOs bind selectively to their target sites at pH 7.4-7.8 in the presence of millimolar concentrations of magnesium. Electrophoretic analysis of triplex formation indicates that specific TFOs bind to their target sites with apparent dissociation constants in the 10(-7)-10(-9) M range. Strand orientation of the bound TFOs was confirmed by attaching eosin or an iron-chelating group to one end of the TFO and monitoring the pattern of damage to the bound duplex DNA. Possible hydrogen-bonding patterns and triplex structures are discussed.

Quenched molecular dynamics is used as a conformational search technique for the constrained cyclic analog [D-Pen2,D-Pen5]enkephalin (DPDPE) in a continuum solvent. The results show a Gaussianlike distribution of conformations as a function of energy, unlike the distributions found for simple liquids which have sharp bands for different crystal forms and broad glasslike states are found. The lowest energy conformers have structural features in common with those obtained from constrained searches based on energy minimization. (Hruby, V. J., L.-F. Kao, B. M. Pettitt, and M. Karplus. 1988. J. Am. Chem. Soc. 110:3351-3359.) Many of the low energy configurations are amphiphilic with the carbonyl groups on one surface and the hydrophobic groups on the other. This supports the conclusions from the previous modeling study, which yielded amphiphilic structures as the most probable conformations of DPDPE when NOE data were included.

The methodological dependence of observed ion-peptide associations in molecular dynamics simulations is investigated. We compare the results from several simulations of a pentapeptide in explicit solvent and salt ions which differ in the their treatment of the long ranged electrostatic interactions. Results for both the Ewald and switching function techniques are presented. It was found that there were important differences between the two methods for the water dipole-dipole temporal and spatial correlations, total dipole moment fluctuations, and self-diffusion constants. Electrostatic potentials calculated in the region of the peptide are also used to illustrate the large differences that can arise from different treatments of the electrostatic interactions. It appears that the switching function distorts the molecular electrostatic potential experienced by the salt ions to such a degree that their behaviour becomes highly dependent on the initial conditions. In summary, the use of a switching function is not recommended for the simulation of ions and their interactions with biomolecules.

The grand molecular dynamics (GMD) method has been extended and applied to examine the density dependence of the chemical potential of a three-site water model. The method couples a classical system to a chemical potential reservoir of particles via an ansatz Lagrangian. Equilibrium properties such as structure and thermodynamics, as well as dynamic properties such as time correlations and diffusion constants, in open systems at a constant chemical potential, are preserved with this method. The average number of molecules converges in a reasonable amount of computational effort and provides a way to estimate the chemical potential of a given model force field.

A reformulation of reference interaction site model theory is proposed. The approach makes use of the formally correct asymptotic form of the correlations obtained from the one-center angular expansion technique. A modified closure, or equivalently, a modified propagation equation for site-site correlations is shown to incorporate the necessary information to allow dielectric consistency in finite-concentration salt solutions. Examples of the correlations and thermodynamics are given.

Recently, oligonucleotides have been shown to inhibit transcription in genes by triple helix or triplex formation in vitro and in vivo. A better understanding of the forces that stabilize triplex structures will be important in developing applications of this method of genetic medication to arbitrary sequences. Therefore, base pairings and strand orientations for homogeneous d(T.A.T)27 and d(C.G.G)27 triplexes were examined. The method was extended to triplex models formed by c-myc gene promoter region and complementary oligonucleotides. Templates of a single plane with three bases were constructed and used in a simple geometric replication based on experimental geometric parameters. Minimizations and quenched molecular dynamics simulations were performed on the model systems. The estimated accessibility of the major groove for counteraction coordination was obtained by calculating the effective accessible surface areas of backbone phosphate oxygen atoms. Free energy calculations of the solvation/desolvation penalty on single strands, duplexes, and the stereoisomeric triplexes have been performed. They were combined with corresponding enthalpic term so that the results could be discussed in a more realistic aspect. For d(T.A.T)27 triplexes, results from both the internal potential energy and solvation free energy calculations contribute to the experimentally known base pairing and strand orientation. Solvation is found to determine the strand orientation for d(C.G.G)27 triplexes with either Hoogsteen or reversed-Hoogsteen base pairing between the two purine strands being possible. We have compared the d(C.G.G)27 triplexes by computing the hydrogen-hydrogen distances which may be useful in verifying these models by future NMR/NOE studies. Using these homopolymers the orientation of oligonucleotides bound to the c-myc gene promoter site is shown to also be dominated by the forces of solvation.

We have used high-temperature quenched molecular dynamics calculations to investigate the conformational properties of tuftsin (Thr-Lys-Pro-Arg) in solution. Conformers obtained after quenching of the dynamical structures were sorted into families depending on their relative energies and backbone conformations. By examination of these families, several cyclic analogues of tuftsin were proposed and examined theoretically by further quenched dynamics simulations. Two of the four proposed analogues were found to adopt essentially identical conformations to that of linear tuftsin. It is suggested that these two derivatives (cyclo[Thr-Lys-Pro-Arg-Gly] and cyclo[Thr-Lys-Pro-Arg-Asp]) may be biologically active, and that the introduction of cyclic conformational constraints should help to reduce the entropic penalty to peptide binding.

Keywords:

The electrostatic contributions to free energies of solvation of several small molecules have been calculated, treating the solvent as a statistical continuum. The computational method is based on solving the linearized Poisson-Boltzmann equation for the electrostatic potentials using the finite-difference scheme. A careful study of convergence indicates the importance of a fine grid spacing, as well as the short comings of rotational averaging. The computed free energies of solvation are in excellent agreement with the experimental results as well as the free energy perturbation calculations. The free energies of hydration of the natural nucleic acid bases are calculated and shown to be somewhat sensitive to charge model.

Alkali liquids intercalated in graphite are subject to a strong periodic host potential. We compare here two theories for the modulation induced in the alkali density that result in different approximations for higher-order correlations, with computer simulations and experimental data. We show these two theories-one based on a cumulant expansion, the other on an angular truncation of the Lovet-Mou-Buff equation-agree analytically in the limit of weak host potential and are numerically similar at high temperatures for a realistic potential.

Because of difficulties associated with experimental measurement techniques, the distribution of water density around many proteins is not well-resolved. We present, in this paper, a molecular dynamics approach to the general problem of comparing the instantaneous vs average view of protein hydration via a 150-ps simulation of metmyoglobin in an explicit aqueous environment. Densities as a function of position for both water and myoglobin were computed by time-averaging the volume fraction occupied at different positions in space. The picture so obtained challenges the view of hydration taken from accessible surface features related to the average structure. A detailed picture of protein hydration is given that includes significant surface penetration and transient channels, in conjunction with the accepted concepts of a-tightly bound partial layer of water on the surface near charged groups.

The potentials of mean force (pmfs) for rotation around the chi1 aromatic side-chain dihedrals of the zwitterionic bis-penicillamine enkephalin pentapeptide have been determined in both aqueous and saline solution. These side chains are known to be associated with the pharmacophore and their conformational populations are thought to be critical for activity. It is found that the association between chloride ions and the peptide in saline solution simulations has profound effects on the relative energies of the g-, g+, and t conformations, and also the barriers between them. Using the pmfs we have also calculated the respective Boltzmann-weighted 3J(alphabeta) vicinal coupling constants. The agreement between the calculated and experimentally determined coupling constants is poor for the pmf in pure water, but substantially improved for the pmf determined in saline solution. Reasons for these differences appear to be related to the experimental conditions.

Dynamics simulations of molecular systems are notoriously computationally intensive, Using parallel computers for these simulations is important for reducing their turnaround time. In this article we describe a parallelization of the simulation program CHARMM for the Intel iPSC/860, a distributed memory multiprocessor. In the parallelization, the computational work is partitioned among the processors for core calculations including the calculation of forces, the integration of equations of motion, the correction of atomic coordinates by constraint, and the generation and update of data structures used to compute nonbonded interactions. Processors coordinate their activity using synchronous communication to exchange data values. Key data structures used are partitioned among the processors in nearly equal pieces, reducing the memory requirement per node and making it possible to simulate larger molecular systems. We examine the effectiveness of the parallelization in the context of a case study of a realistic molecular system. While effective speedup was achieved for many of the dynamics calculations, other calculations fared less well due to growing communication costs for exchanging data among processors. The strategies we used are applicable to parallelization of similar molecular mechanics and dynamics programs for distributed memory multiprocessors.

A liquid state theory based on site-site integral equations is constructed to have the asymptotics given by angular expansion theory. This results in a theory which shows dielectric consistency, e.g., the dielectric constant as viewed from the solvent is the same as that viewed by the ions. Such consistency is lacking in other extended reference interaction site model (XRISM)-based theories and leads to unrealistic structural predictions. The Kirkwood-Buff route to thermodynamics is used and allows a physical partitioning of the terms responsible for the solvation process. Sample results for a 1-1 salt are given.

In this paper we report the initial steps in the development of a Monte Carlo method for evaluation of real-time Feynman path integrals for many-particle dynamics. The approach leads to Gaussian importance sampling for real-time dynamics in which the sampling function is short ranged due to the occurrence of Gaussian factors. These Gaussian factors result from the use of a generalization of our new discrete distributed approximating functions (DDAFs) to continuous distributed approximating functions (CDAFs) so as to replace the exact coordinate representation free-particle propagator by a CDAF-class, free-particle propagator which is highly banded. The envelope of the CDAF-class free propagator is the product of a bare Gaussian, exp[-(x'- x)2sigma2(0)/(2sigma4(0) + H2tau2/m2BAR)], with a shape polynomial in (x' - x)2, where sigma(0) is a width parameter at zero time (associated with the description of the wavepacket in terms of Hermite functions), tau is the time step (tau = t/N, where t is the total propagation time), and x and x' are any two configurations of the system. The bare Gaussians are used for Monte Carlo integration of a path integral for the survival probability of a Gaussian wavepacket in a Morse potential. The approach appears promising for real-time quantum Monte Carlo studies based on the time-dependent Schrodinger equation, the time-dependent von Neumann equation, and related equations.

We report the calculated characteristics of nonnatural triplex-forming oligonucleotide (TFO) bases recognizing base-pair reversals (TA -> AT) in a double-helical DNA sequence. Ab initio and molecular mechanics calculations have been carried out to characterize the geometric and energetic consequences at the base-pair reversal sites. We have estimated the free energies of solvation of the natural and proposed bases by solving the linearized Poisson-Boltzmann equation. The calculations indicate that the proposed TFO bases should bind with some specificity to the duplex. Implications of the strategy used in the context of molecular biology is discussed. (C) 1993 John Wiley & Sons, Inc.

Langevin dynamics on a potential of mean force energy surface is used to model the effects of aqueous solvent on the structure and dynamics of the alanine dipeptide. Conformational transition rates obtained by correlation function analysis and hazard plots from several simulations are compared. In particular, averages obtained over three 25-ns runs are compared with a single run of 100 ns. Rate constants for selected conformational transitions are also examined. For the conformational processes considered here (alpha to beta and the reverse), we observe two rates, one of which is only significant for simulations of more than 25 ns. On further decomposition of the rate process, it is shown that the two observed rates correspond to the individual rates for rotation around the phi and psi dihedrals. It is also shown that, for the conformational transitions investigated here, the transition process corresponds to an essentially uncorrelated motion of the two dihedral angles.

We report a novel conformational search procedure that is used to investigate the binding mechanism of a member of the WIN class of antiviral compounds. A simple hypothesis of important residues in the binding site based on differences in drug-free and drug-bound X-ray structures along with more elaborate models, ultimately including the entire virus, is considered. Our search method is a variant of slow-growth molecular dynamics used in free energy simulations and gives rise to local motion in the protein backbone of up to 3 angstrom. This technique involves the scaling of drug-protein interaction energies over time periods of 10-100 ps and gives rise to local motion in the protein backbone. In addition, we have used high-temperature dynamics with periodic quenching to generate low-energy conformations with backbone displacements in the crystallographic binding region of up to 7 angstrom from the native structure. Mechanism of binding, hydrogen-bond stabilization of active-site conformations, concerted drug-protein motions, and the mode of virion stabilization are addressed in relation to our ligand induced and high-temperature conformational search procedures. A loop-cap like mechanism is consistent with the results of our study. A large movement of the 'active-site'' residues is shown to be theoretically possible and provides a greater access for entry of the drug into its binding pocket than seen in the available crystal structures.

The bis(penicillamine) enkephalin, a small zwitterionic pentapeptide, has been studied in explicit 1.0 M sodium acetate solution with use of the molecular dynamics technique. During the simulation the association of multiple acetate ions with the positively charged N terminal region was observed. In addition, but to a far lesser extent, sodium ion binding to backbone carbonyl groups close to the negatively charged C terminus also occurred. Interesting individual events, such as the simultaneous binding of an acetate to a hydrogen of the N terminus and to backbone NH groups, were observed. Most often acetates only associated with the N terminal hydrogens. Subtle conformational changes in the peptide backbone were found as a consequence of acetate binding. These mechanistic observations are consistent with, and may be rationalized by, the known salting in and salting out properties of these ions and their relative positions in the Hofmeister (lyotropic) series.

We report the results of a 100-ps molecular dynamics simulation study of triple helical DNA with explicit water, counterions, and salt using periodic boundary conditions at 300 K. The simulation involved an antiparallel reverse-Hoogsteen-like homopolymeric CGG 7-mer triple helix, 837 water molecules, 21 Na+ ions, and 1 M NaCl. We have used the Ewald method to compute the electrostatic interactions. Specific ion and water associations as well as relative solvent and ion mobilities are reported. Specific patterns of ion and water molecule associations are found which are novel and may have implications for stability and recognition of triplex-forming oligonucleotides by duplex DNA. Exchanges of ions around neighboring phosphate were found to correspond to a concerted mechanism of displacement. Comparisons are made with available data from related systems.

An oligonucleotide hybrid is described which possesses two triple helix forming oligonucleotides which have been connected by a flexible polymeric linker chain. As a prototype, binding of this class of oligonucleotide to duplex DNA has been studied using a segment of the HSV-1 D-glycoprotein promoter, which possesses a pair of 12bp target sites for stable triple helix formation, separated by a duplex spacer region which is one helical turn long. Band shift and footprinting analysis show that such hybrids can bind to both 12bp elements simultaneously, if flexible linkers are included which are longer than 20 - 25 rotatable bonds. Molecular modeling confirms that a flexible polymeric linker as short as 22 rotatable bonds is enough to link the two distant segments of triple helix, providing that the linker element travels a path which is external to the helix grooves and parallel to the long helix axis.

The results of this theoretical study combining sequence analysis and minimization with integral equation liquid structural methods indicate that the local sequence context of a T-G wobble mismatch influences the local conformation of the helix, and that conformational alterations are correlated with mutational activity. Studies on the mismatch in four different 5' and 3' neighbor contexts indicate that the nature of the 5' base to the thymine of the mispair is probably the single most critical factor in determining the structural features that facilitate or discourage mutations. When cytosine is the 5' neighbor, the helix adopts a mostly BII conformation, whereas a 5' guanine preserves the canonical BI. Structures that vary little from the BI structure on the incorporation of the mismatch have sequences that correspond to lower rates of transition, whereas those with mostly BII conformations, have sequences with high mutation rates. Subtle variations in stacking patterns around the mismatch precipitate a structural Domino-effect, with a variety of changes in conformation. The helix opens at the mismatch with increased roll angle and propeller twist, causing the thymine to migrate into the major groove and the guanine into the minor groove, exposing the heteroatomic groups to the solvent in the major and minor grooves, respectively, and allowing for some unusual hydrogen bonds. These alterations show a tentative correlation with mutation rates, implying that stacking and structure around the mismatch are important features in the discrimination by proofreading activities of canonical W-C and wobble mismatch base pairs during replication-repair. Variations in the C1'-C1' distances, high propeller twists, changes in the electrostatic complementarity leading to unusual hydrogen bonding patterns probably all correlate with detectability.

An analysis of a molecular dynamics simulation of metmyoglobin in an explicit solvent environment of 3,128 water molecules has been performed. Both statics and dynamics of the protein-solvent interface are addressed in a comparison with experiment. Three-dimensional density distributions, temperature factors, and occupancy weights are computed for the solvent by using the trajectory coordinates. Analysis of the hydration leads to the localization of more than 500 hydration sites distributed into multiple layers of solvation located between 2.6 and 6.8 Angstrom from the atomic protein surface. After locating the local solvent density maxima or hydration sites we conclude that water molecules of hydration positions and hydration sites are distinct concepts. Both global and detailed properties of the hydration cluster around myoglobin are compared with recent neutron and X-ray data on myoglobin. Questions arising from differences between X-ray and neutron data concerning the locations of the protein-bound water are investigated. Analysis of water site differences found from X-ray and neutron experiments compared with our simulation shows that the simulation gives a way to unify the hydration picture given by the two experiments. (C) 1994 Wiley-Liss, Inc.

The dynamics of water at the protein-solvent interface is investigated through the analysis of a molecular dynamics simulation of metmyoglobin in explicit aqueous environment. Distribution implied dynamics, harmonic and quasiharmonic, are compared with the simulated macroscopic dynamics. The distinction between distinguishable solvent molecules and hydration sites developed in the previous paper is used. The simulated hydration region within 7 Angstrom from the protein surface is analyzed using a set of 551 hydration sites characterized by occupancy weights and temperature B-factors determined from the simulation trajectory. The precision of the isotropic harmonic and anisotropic harmonic models for the description of proximal solvent fluctuations is examined. Residence times and dipole reorientation times of water around the protein surface are compared with NMR and ESR results. A correlation between diffraction experiment quantities such as the occupancy weights and temperature factors and the residence and correlation times resulting from magnetic resonance experiments is found via comparison with simulation. (C) 1994 Wiley-Liss, Inc.

The solvent structure and dynamics around myoglobin is investigated at the microscopic level of detail by computer simulation. We analyze a molecular dynamics trajectory in terms of solvent mobility and probability distribution. Local events, occurring in the protein-solvent interfacial region, which are often masked by other approaches are thus revealed. Specifically, the local solvent mobility is greatly enhanced for certain locations at the protein surface and in its interior. In addition, a strong correlation between the solvent mobility and density emerges on both global and local scales. We propose a simple model where the solvent distribution measured perpendicularly to the protein surface is utilized to reconstruct the simulated network of hydration within 6 Angstrom from the protein surface with a relative error of only 17 model matches results obtained with more complicated models usually used in refinement procedures in x-ray and neutron experiments but with far fewer parameters. The dramatically improved correspondence between observed and calculated x-ray intensities at low resolution relative to other methods both confirms the validity of the approach used in the MD (molecular dynamics) simulations and allows the results of this study to be implemented in solvent studies on real systems.

The existence of a high-density phase separation for molecular and continuum solvent models of ion-water solutions are demonstrated using the DRISM/HNC theory. The molecular lever effects which influence solubility and the inability of continuum models to exhibit some of these effects are discussed. The general trends in experimental alkali halide solubilities are found to be consistent with the present model calculations. The dependence of the phase separation on ion size is found to be primarily entropic in nature.

The grand molecular dynamics (GMD) method has been extended and applied to examine the chemical potential and temperature dependence of a three-site water model in dense phase. The study demonstrates the utility of GMD in the study of phase transitions. Cuts through the phase diagram of water in terms of temperature, as well as excess chemical potential, are obtained. The density maximum of water just above freezing is well reproduced. High-pressure glass forms of solid ice are also examined.

Binding energies, intermolecular distances, and partial charges from ab initio studies of SO42- + H2O were used to develop a molecular mechanics model for SO42- in water. Structural, dynamic, and thermodynamic properties for the resulting model used in condensed-phase simulations agree well with experimental estimates. Thirteen waters are found to be present in the first solvation shell, and the residence time of these waters has been calculated to be 23 ps. The model anion has a free energy of solvation relative to xenon of -275 kcal mol(-1), which compares well with the experimental estimate of -266 kcal mol(-1).

Results for free energy, entropy, enthalpy and internal energy of solvation for monovalent ions in water have been studied by comparing DRISM theory results to those of RISM and ARISM theories. The greatly improved dielectric behavior in the DRISM case enabled the examination of realistically modeled salts at finite concentrations. The link between solvent structure and the entropy of solvent co-spheres was examined. Finally comparison with the Born free energy equation shows its virtues and flaws due to ignoring cavity formation and asymmetric solvation terms which together always contribute significantly to the free energy of hydration of ions.

An extended system Hamiltonian for the grand canonical ensemble that includes the number dependence of the ideal chemical potential is investigated. Use of the ideal contribution explicitly in the equations of motion provides simpler and more stable equations of motion than previous grand molecular dynamics methods. We find the equations of motion remain quite stable even in gaseous conditions where mean field treatments of the ideal contribution provide a trivial result. The equations of motion are solved in real variable space as opposed to using virtual variables. Application of this simulation method with a Lennard-Jones fluid in the gas, fluid and solid phases is demonstrated.

The molecular origins of the common ion effect and the salting out of nonpolar molecules from aqueous solutions are investigated. Thermodynamic stability criteria for a common ion mixture in a polar solvent are derived. Kirkwood-Buff statistical thermodynamics is used to make the connection with the microscopic pair correlation functions. The observed sensitivity of the compositional stability with respect to ionic strength indicates that a demixing transition is the primary cause of the instability for the common ion effect for our model Lennard-Jones plus Coulomb Hamiltonian.

Currently applied models for the treatment of solvent in biomolecular systems are reviewed. Solvent models ranging from purely continuum to quantum mechanical in nature are discussed, together with their ranges of validity and the approximations inherent to the various methods. As a potential energy surface interpretation of thermodynamics and kinetics is a useful and familiar tool to the physical chemist; we use the generalization to free energy surfaces (or potentials of mean force) to unify the discussion where possible. An example of how theory and simulations can aid in the interpretation of experimental data for the solvation of myoglobin is presented. It is argued that the advent of better theories and increasingly faster computers will provide the opportunity for the application of more rigorous solvent models for the study of complex biomolecular solutions with increasingly more accurate results.

The dynamic equilibrium that exists in a chemically reacting system can be simulated using classical mechanics if the appropriate statistical mechanical ensemble is chosen. This paper describes a general method that makes it possible to simulate this equilibrium in a simple chemical reaction through the use of a recently developed grand canonical molecular dynamics method. After a brief description of the method, an example calculation is performed that simulates the acid-base equilibrium between acetic acid and water. The computational demands of this application are discussed along with a description of a new MPP algorithmic approach to this application.

The conformational influences of (2S,3S)-2,3-methanomethionine ((2S,3S)-cyclo-Met or (2S,3S)-cyclo-M) were studied to ascertain possible effects of substituting such constrained amino acids into small peptides. The peptide chosen for study was the anti-opiate Phe-Met-Arg-Phe-NH2 (FMRF-NH2 using the one-letter code). Consequently, FMRF-NH2 and F((2S,3S)-cyclo-M)RF-NH2 were prepared, and studied by NMR in DMSO. Protons of the parent peptide had no anomalous chemical shifts, no shallow temperature coefficients for variations of NH chemical shifts with temperature, and no interresidue ROE cross-peaks except for the sequential backbone signals. These results were as expected for a random coil conformation. Conversely, F((2S,3S)-cyclo-M)RF-NH2 gave NMR spectra with indications of a bias toward defined secondary structures in solution. Computer-assisted molecular simulations were carried out to visualize these conformational biases. Thus, parameters for the 2,3-methanoamino acid were developed using literature values for bond vectors from crystallography, and CHARMM defaults. The validity of these parameters was accessed from Ramachandran plots for derivatives of the type Ac-(cyclo-M)-NHMe. These parameters were then used for a comparative quenched molecular dynamics (QMD) study of FMRF-NH2 and F((2S,3S)-cyclo-M)RF-NH2, without invoking constraints from the NMR data. Data (presented as phi, psi dot plots) from the downloaded simulated conformations at 1000 K, and for the energy-minimized forms of these conformations, could be easily rationalized on the basis of reasonable conformational biases about the amino acid residues. The rigidly oriented side chains of the (E)-cyclo-Met derivative (wherein The alpha-amino group and the side chain are trans with respect to the cyclopropane ring) had a more severe effect on the allowable psi values than on the psi torsions. The lowest energy structures generated in the dynamics run after minimization were grouped into families to give representations of related conformers. Finally, the results from the NMR and QMD studies were compared. For F((2S,3S)-cyclo-M)RF-NH2 a good correlation was found, indicating a bias toward a gamma-turn structure in solution. We predict that (E)-cyclo-Met residues in larger peptides could induce formation of turn or 3(10)-helical structures.

The ordinary differential equations of Newtonian dynamics are used in atomic simulations with the method of molecular dynamics. The basic issues are surveyed and standard algorithms are described. Several algorithmic variants are discussed. Some advanced ideas relating to parallel computation are considered.

Thermodynamic stability and Statistical mechanical theory are applied to a model of a zwitterionic tripeptide of sequence Gly-Ala-Gly in high-concentration NaCl solution. It is found that many peptide conformations cannot exist in equilibrium with the salt-water solvent as a single liquid phase. This suggests a single explanation for salting proteins into and out of solution, unique biologically active protein structures, and small energy differences between denatured and folded states, while also implying a mechanism for the resolution to the Levinthal paradox.

The interplay between simulations at various levels of hydration and experimental observables has led to a picture of the role of solvent in thermodynamics and dynamics of protein systems. One of the most studied protein-solvent systems is myoglobin, which serves as a paradigm for the development of structure-function relationships in many biophysical studies. We review here some aspects of the solvation of myoglobin and the resulting implications. In particular, recent theoretical and simulation studies unify much of the diverse set of experimental results on water near proteins.

The structure and stability of a DNA triple helix was examined by molecular dynamics (MD) simulation using an all-atom force field. A 1.3 ns simulation was performed on a d(CG . G)(7) triple helix in a 1 M saltwater solution. The Ewald method was used to calculate the electrostatic interactions of the system. The behavior of the DNA in the saltwater solution was determined by examining the structure, energetics, and mobility of water and ions in the system. The simulation results for the helical parameters support the validity of a model-built triplex-DNA structure. A low root mean square deviation of the dynamic structure from the initial structure demonstrates the stability of the tripler in the salt solution. The sugar pseudorotation, the backbone conformations, and the average helical parameters suggest that the conformation of strands I and III is strictly neither A-form nor B-form, whereas the conformation of strand II remains near the A-form. A higher mobility of both the cytosine strand and the triplex-forming guanine strand and also a longer residence time of water molecules in the spine of hydration were observed and are consistent with available NMR results.

Integral equations of the Ornstein-Zernike (OZ) type have been useful constructs in the theory of liquids for nearly a century. Only a limited number of model systems yield an analytic solution; the rest must be solved numerically. For anisotropic systems the numerical problems are heightened by the coupling of more unknowns and equations. A matrix method for solving the full anisotropic OZ integral equation is presented. The method is compared in the isotropic limit with traditional approaches. Examples are given for a 1-D fluid with a corrugated (periodic) external potential. The full two point correlation functions for both isotropic and anisotropic systems are given and discussed.

We report the results of a theoretical study, combining the results of sequence analysis and integral equation structural methods for nucleic acids in aqueous solutions, on the effects of nearest neighbors on the (T . G) mispair in solution, for 12 nearest neighbor contexts. Attempts have been made to classify the structural and energetic effects of the 5' and 3' neighbors with respect to the observed spontaneous mutation rates in vertebrates. It is found that 5' nearest neighbor is probably the mast critical structural factor in facilitating or discouraging mutations. Local conformational states correlate with discrimination of bases to be excised in mispairs. Our study confirms the role of the flexibility of the DNA molecule in governing the rates of spontaneous mutations. (C) 1995 John Wiley & Sons, Inc.

Using free energy molecular mechanics, we find that the molecular effects of solvent are critical in determining relative stabilities in DNA triple helices or triplexes. The continuum solvent model is unable to differentiate the thermodynamics reflecting the basic solvation differences around the occupied major groove in triplexes. In order to avoid the local minimum problem, which is a major limitation of any modeling study, we started our computations with multiple structures rather than relying on the optimization of a single reference structure. By constructing triplex models with different initial helical twists, helical rises, and sugar-pucker permutations, we explore the potential surface and the structural preference with respect to these variations. We find that in order to accommodate a third strand in triplex formation, the backbone geometry of the B-DNA duplex target has to be adjusted into A-DNA-like form with a deep major groove. This is achieved by concerted adjustment in torsions beta, epsilon, and zeta around the phosphate groups. However, the sugar pucker displays a more rich variation, resulting in conformations not usually associated with the canonical duplex structures. (C) 1995 John Wiley & Sons, Inc.

Correlations in low-frequency atomic displacements predicted by molecular dynamics simulations on the order of 1 ns are undersampled for the time scales currently accessible by the technique. This is shown with three different representations of the fluctuations in a macromolecule: the reciprocal space of crystallography using diffuse x-ray scattering data, real three-dimensional Cartesian space using covariance matrices of the atomic displacements, and the 3N-dimensional configuration space of the protein using dimensionally reduced projections to visualize the extent to which phase space is sampled.

A method is described which improves the efficiency of Ewald simulations of large condensed phase systems. This is achieved by partitioning the real space sum into a short and long range component. The long range component is calculated every time the pair list is generated and included in subsequent steps using a multiple time:step algorithm. The corresponding increase in the effective cutoff distance results in an algorithm which is only slightly more expensive than a traditional cutoff simulation, but with fewer artifacts than obtained using a cutoff. The method is tested on a 1.0M solution of sodium chloride.

We have analyzed a 1.2-ns molecular dynamics simulation of 51 mM d(CG-G), with 21 Na+ counter-ions and 1 M NaCl in water. Via the dipole fluctuations, the dielectric constant for the DNA is found to be around 16, whereas that for the bases and sugars combined is only 3. The dielectric constant for water in this system is 41, which is much smaller than 71 for pure SPC/E water, because of the strong restriction imposed on the motion of water molecules by the DNA and the ions. Also addressed in the present work are several technical issues related to the calculation of the dipole moment of an ionic solution from molecular dynamics simulations using periodic boundary conditions.

The conformational properties of the configurational isomers of tuftsin, a linear tetrapeptide with the sequence Thr-Lys-Pro-Arg, were investigated with six 1 ns molecular dynamics simulations in explicit water and in a 1.0 M NaCl solution. The average conformation of the cis isomer is a type VI beta-turn. Our results indicate that water-peptide hydrogen bonding, in addition to intramolecular hydrogen bonds, stabilizes the cis conformer, The trans isomer is neither a beta- nor a gamma-turn. Results are compared with parallel studies on a cyclic analog of tuftsin, cyclo (Thr-Lys-Pro-Arg-Gly). The addition of salt does not influence the backbone conformation of the peptide. Differences between the structures are confined to the side-chain orientations of the Lys and Arg residues. (C) Munksgaard 1995.

A 3.5-ns atomic-level computer simulation of a DNA solution was performed. We found that a dodecamer of DNA, which contains the recognition site for Eco RI endonuclease, transforms from B-form to A-form in 0.45 M salt water. This supports an earlier proposal on the A-DNA binding site for transcription factor IIIA.

The dielectrically consistent interaction site model theory is applied to a model system consisting of a zwitterion tripeptide of sequence Gly-Ala-Gly at infinite dilution in a solvent mixture of water and sodium chloride with only the central phi,psi, dihedrals for conformational degrees of freedom. The peptide is found to be salted into solution by the cosolvent, with its solubility depending strongly on conformation of the central phi,psi pair. The distribution of cosolvent relative to the bulk solvent mixture is examined and relatively little specific association is found. Instead, the ionic concentration around the peptide is increased, especially near the phase boundary, and the increased concentration extends up to eight solvent diameters into the bulk. The consequences of such an ionic distribution on thermodynamic measures of association are discussed. Similarities between this model system and the unusual solubility behavior of beta-lactoglobulin found in experiments are shown. The molecular distributions calculated are found to be consistent with a separation of the solvent mixture into two non-miscible phases, one of which contains the solute and has a higher cosolvent concentration than the other. Since turbid solutions have been observed in the beta-lactoglobulin system, it is suggested that a separation into two liquid phases could be common to both systems.

The dielectrically consistent reference interaction site model theory (DRISM) was used to calculate excess chemical potentials of solvation for the immersion of a nonpolar solute molecule (Lennard-Jones sphere) in a molecular model of water in a wide variety of state conditions. The chemical potential was found to be predominantly entropic, In all cases the chemical potential was found to consist almost entirely of a solute surface area and a solute volume term. Both these terms were significant over a range of solute sizes and pressure/temperature states. It was concluded that the volume-dependent term must include contributions in addition to that from the system pressure. An exactly solvable lattice model of solvation was also investigated, and the model conditions for which the chemical potential becomes predominantly entropic were determined. One situation was shown where a volume-dependent entropic term in the chemical potential, other than pressure, arises.

A 1.5 ns long molecular dynamics simulation was conducted to compare the structure and stability of model DNA tripler in saline solution with that found from experiments. The model DNA was an antiparallel py . pu . pu (CG . G) 7-mer structure which contained a GC . T mismatch triplet at the middle of the sequence. The local conformation of the mismatch tripler and the effects of this triplet on the global helical structure suggest that the GC . T triplet forms stable hydrogen bonds and shows distortions from an in-plane alignment. The overall rms deviation of the tripler is similar to one without a mismatch, although the thymine base in the mismatch triplet shows significantly higher mobility. A high coordination probability for water between the G and T bases in the mismatch tripler was observed to have an effect on the stability of non-hydrogen-bonded base pairs. Average helical parameters, sugar pucker, and backbone dihedral angles indicate that the CG . G triplets on the 3' side of the mismatch triplet possess different structural and dynamical properties than that of the 5' side. These observations are consistent with recently available experimental results and provide an interpretation of the observed experimental structure. They also suggest that inclusion of explicit water molecules is necessary in order to understand and predict the interaction between the third strand and duplex DNA.

We have reviewed aspects of the medicinal chemistry of Tuftsin. Biochemical and clinical aspects including physioogy and assays are briefly accounted for. Structure-activity relationships found in the literature provide a link between the synthetic/design strategies and the biological response, Directed rational design and synthetic techniques are reviewed for both tuftsin and its analogs.

Four 1-ns molecular dynamics computer simulations of tuftsin, Thr-Lys-Pro-Arg, are analyzed: (1) cis tuftsin in water, (2) trans tuftsin in water, (3) cis tuftsin in 1 M NaCl, and (4) trans tuftsin in 1 M NaCl. Independently of the salt concentration, the trans conformer has a higher dielectric constant than the cis conformer because the former exhibits a more widely distributed charge distribution in space. Independently of the peptide conformation, the presence of salt reduces the dielectric constants of both the peptide and the solvating water molecules because ions, on binding, restrict the motion of other atoms. In contrast to the dielectric constants, neither the peptide conformation nor the salt concentration shows a significant influence on the dielectric relaxation time of water molecules.

An investigation into the effects of the anisotropic nature of the Ewald potential for the treatment of long range electrostatic interactions in liquid solutions has been performed. The rotational potential energy surface for two simple charge distributions, and a small protein, have been studied under conditions typically implemented in current biomolecular simulations. A transition between hindered and free rotation is observed which can be modeled quantitatively for simple charge distributions. For most systems in aqueous solution, the transition involves an energy change well below k(B)T. It is argued that, for solvents with a reasonably high relative permittivity Ewald artifacts will be small and in many cases may be safely ignored. (C) 1996 American Institute of Physics.

We extend the technique of using perpendicular distribution functions to salt solutions around nucleic acids. Both solute density averaged and nonaveraged reference frames are considered and compared. Using a previous simulation of DNA in salt water of over a nanosecond in duration, the aqueous distribution functions were found to be well converged, whereas the salt perpendicular distribution functions were less well determined. Three-dimensional density reconstructions reliably showed the prominent solvation features with transferable functions. The number of solute atom types needed for reconstructions of a given precision was determined in the context of the reference simulation data set with the goal of achieving a required level of reconstruction quality. (C) 1997 John Wiley & Sons, Inc.

A simple method is presented for projecting the conformation of extended secondary structure elements of peptides and proteins that extend over four C-alpha atoms onto a simple two-dimensional surface, A new set of two degrees of freedom is defined, a pseudo-dihedral involving four sequential C-alpha atoms, as well as the triple scalar product for the vectors describing the orientation of the three intervening peptide groups, The method provides a reduction in dimensionality, from the usual combination of multiple phi,psi pairs to a single pair, yielding valuable information concerning the structure and dynamics of these important elements. The new two dimensional surface is explored by reference to 63 selected protein crystal structures together with a comparison of model built peptides representing the common secondary structural elements, Dynamical aspects on this new surface are examined using a molecular dynamics trajectory of Basic Pancreatic Trypsin Inhibitor. (C) 1997 Wiley-Liss, Inc.

The electrostatic potential and component dielectric constants from molecular dynamics (MD) trajectories of tuftsin, a tetrapeptide with the amino acid sequence Thr-Lys-Pro-Arg in water and in saline solution are presented. The results obtained from the analysis of the MD trajectories for the total electrostatic potential at points on a grid using the Ewald technique are compared with the solution to the Poisson-Boltzmann (PB) equation. The latter was solved using several sets of dielectric constant parameters. The effects of structural averaging on the PB results were also considered. Solute conformational mobility in simulations gives rise to an electrostatic potential map around the solute dominated by the solute monopole (or lowest order multipole). The derailed spatial variation of the electrostatic potential on the molecular surface brought about by the compounded effects of the distribution of water and ions close to the peptide, solvent mobility, and solute conformational mobility are not qualitatively reproducible from a reparametrization of the input solute and solvent dielectric constants to the PB equation for a single structure or for structurally averaged PB calculations. Nevertheless, by fitting the PB to the MD electrostatic potential surfaces with the dielectric constants as fitting parameters, we found that the values that give the best fit are the values calculated from the MD trajectories. Implications of using such field calculations on the design of tuftsin peptide analogues are discussed. (C) 1999 John Wiley & Sons, Inc.

We evaluate two different ways of calculating the contribution of the electrostatic stress to the free energy integral based on Sharp and Honig's method within the finite difference nonlinear Poisson-Boltzmann equation method with the University of Houston Brownian Dynamics program. We show that only one of these approaches gives consistent results in the limit of zero ionic concentration for interactions of the order of magnitude of the hydrogen bond. The results are compared with results from both the linear Poisson-Boltzmann equation and the Debye-Huckel theory, for ion concentrations within the limits of validity of these approximate methods. We demonstrate this by application to DNA molecules. (C) 1997 Academic Press.

The presence of Ewald artifacts in a molecular dynamics simulation of a zwitterionic tetrapeptide in aqueous solution has been investigated. Both equilibrium and dynamical aspects of the rotational behavior of the peptide were examined. The equilibrium distribution of rotational states obtained from a 10 ns simulation were consistent, within statistical errors, with a random distribution free from Ewald artifacts. The rotational dynamics of the peptide was observed to obey simple Debye diffusion with a rotational diffusion rate in agreement with that predicted by a simple rotational diffusion model assuming no substantial long-lived water hydration shell. These results suggest that rotational Ewald artifacts will be negligible for small biomolecular simulations in solvents with high relative permittivities. The data support the results obtained from a previous study of simpler model systems.

The first two orders of bridge diagrams, those with two and three field points, have been calculated exactly for the Lennard-Jones fluid for several isotherms. The method of calculation was one of expansion in Legendre polynomials, and the dependence of the method on the number of polynomials needed for accurate results was investigated. Thermodynamic and structural properties of the Lennard-Jones fluid calculated from integral equation methods with the inclusion of bridge diagrams were found to be systematically improved. Two attempts at predicting the missing bridge diagrams of even higher order were discussed. The first, which uses the functional form of those diagrams that were calculated exactly, showed no significant improvement. The second, a series sum based on the first two orders of calculated diagrams and motivated by the success of a similar heuristic sum in the case of hard spheres, was extremely successful. When the series sum was employed, thermodynamic and structural quantities were improved to the point where the difference between simulation results and integral equation results was of the same order as the error in the simulations themselves.

The effect of terminal group charge on the structure and dynamics of the alanine tetrapeptide has been investigated using molecular dynamics simulations. Neutral and positive N-termini, together with neutral and negative C-termini, were studied, resulting in a total of four 10 ns simulations with different terminal group charge combinations. Analysis of these simulations indicates that the terminal group charge has only a minor effect on the conformations sampled for the central dihedrals, but a significant effect on the population distribution of the dihedrals close to the terminal groups. The conformational distribution at the C-terminus (psi 3) was also found to depend on the charge at the N-terminus. Here, the differences result from the formation of transient ion pairs (salt bridges) in the zwitterion case. However, equilibrium sampling of these intramolecular ion pairs was still not fully converged even after 10 ns.

The extended system Hamiltonian for carrying out grand canonical ensemble molecular dynamics simulations is reformulated. This new Hamiltonian includes a generalized treatment of the reference state partition function of the total chemical potential that reproduces the ideal gas behavior and various previous partitionings of ideal and excess terms. Initial calculations are performed on a system of Lennard-Jones particles near the triple point and on liquid water at room temperature. (C) 1997 American Institute of Physics. [S0021-9606(97)52641-9].

We have recently indicated preliminary evidence of different equilibrium average structures with the CHARMM and AMBER force fields in explicit solvent molecular dynamics simulations on the DNA duplex d(C5T5).d(A(5)G(5)) (Feig, M. and B. M. Pettitt, 1997, Experiment vs. Force fields: DNA conformation from molecular dynamics simulations. J. Phys. Chem. B. 101:7361-7363). This paper presents a detailed comparison of DNA structure and dynamics for both force fields from extended simulation times of 10 ns each. Average structures display an A-DNA base geometry with the CHARMM force field and a base geometry that is intermediate between A- and B-DNA with the AMBER force field. The backbone assumes B form on both strands with the AMBER force field, while the CHARMM force field produces heterogeneous structures with the purine strand in A form and the pyrimidine strand in dynamical equilibrium between A and B conformations. The results compare well with experimental data for the cytosine/guanine part but fail to fully reproduce an overall B conformation in the thymine/adenine tract expected from crystallographic data, particularly with the CHARMM force field. Fluctuations between A and B conformations are observed on the nanosecond time scale in both simulations, particularly with the AMBER force field. Different dynamical behavior during the first 4 ns indicates that convergence times of several nanoseconds are necessary to fully establish a dynamical equilibrium in all structural quantities on the time scale of the simulations presented here.

Recent advances in the experimentally determined structures and dynamics of the domains within Lad provide a rare context for evaluating dynamics calculations. A 1500-ps trajectory was simulated for a variant of the Lad DNA-binding domain, which consists of the first three helices in Lad and the hinge helix of the homologous PurR. Order parameters derived from dynamics simulations are compared to those obtained for the Lad DNA-binding domain with N-15 relaxation NMR spectroscopy (Slijper et at., 1997. Biochemistry. 36:249-254). The MD simulations suggest that the unstructured loop between helices II and III does not exist in a discrete state under the conditions of no salt and neutral pH, but occupies a continuum of states between the DNA-bound and free structures. Simulations also indicate that the unstructured region between helix ill and the hinge helix is very mobile, rendering motions of the hinge helix essentially independent of the rest of the protein. Finally, the a-helical hydrogen bonds in the hinge helix are broken after 1250 ps, perhaps as a prelude to helix unfolding.

Conformational searching, computer simulations, synthesis, and NMR are used on a variety of alpha melanocyte-stimulating hormone (alpha-MSH) analogues to understand the physical characteristics required for biological potency. Peptides I(Ac-[Nle(4),Asp(5),D-Phe(7),Lys(10)]alpha-MSH(4-10)-NH2),II(Ac-c[Nle(4) ,Asp(5),D-Phe(7),Lys(10)]alpha-MSH(4-10)-NH2) and III (Ac-[Nle(4),Asp(5),D-Phe(7),Dap(10)]alpha-MSH(4-10)-NH2 all show very similar conformational properties (backbone and side-chain torsional angles), and all display high biological potencies. The modeling results for these compounds are supported by the NMR data. Peptide IV (Ac-c[Nle(4),Asp(5),D-Phe(7),Dap(10)]alpha-MSH(4-10) appears to have a markedly different conformation and has decreased biological potency.

Using molecular dynamics simulations of fully hydrated proteins and analysis of crystal structures contained in the Protein Data Bank, we develop a transferable set of perpendicular radial distribution functions for water molecules around globular proteins. These universal functions may be used to reconstruct the unique three-dimensional solvent density distribution around every individual protein with a modest error. We discuss potential applications of this solvent treatment in protein x-ray crystallographic refinements and in theoretical modeling. We also present a fast, grid-based algorithm for construction of the perpendicular solvent density distributions. (C) 1998 John Wiley & Sons, Inc.

Models of protein hydration are becoming increasingly more accurate in comparison with experimental data. The recent success of these models implies that the major features of the solvation layers are dominated by local correlations and that such correlations are universal. The excellent agreement between theoretical and experimental solvent electron density radial distributions marks a significant success in our ability to accurately model macromolecular hydration.

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Effects of the macromolecular solute on the translational mobility of surrounding solvent water, and Na+ and Cl- ions are investigated by molecular dynamics (MD) simulation. Using MD trajectories of myoglobin and d(C5T5).d(G(5)A(5)) DNA decamer of high quality and length, we determine the average diffusion coefficients for all solvent species as a function of distance from the closest solute atom. We examine solvent mobility in the directions parallel and perpendicular to the solute surface and in proximity to three different classes of solute atoms (oxygens, nitrogens, and carbons). The nature and the magnitude of the solute effects on water diffusion appear to be very similar for protein and DNA decamer. The overall diffusion rate at the interface is lower than in the bulk. The rate is higher than the average in the direction parallel to the solute surface, and lower in the direction normal to the surface, up to 15 Angstrom away from the solute. The rate is also lower in the solvation shells of the macromolecules, producing characteristic depressions in the radial profiles of the diffusion coefficient that can be correlated with peaks in the corresponding radial distribution functions. The magnitude of these depressions is small compared to the overall change in solvent mobility at the interface. Similar features are observed in the radial profiles of the diffusion coefficient of sodium and chlorine ions as well.

Background: The massive amount of information generated from current molecular dynamics simulations makes the data difficult to analyze efficiently. Principal component analysis has been used for almost a century to detect and characterize data relationships and to reduce the dimensionality for problems in many fields. Here, we present an adaptation of principal component analysis using a partial singular value decomposition (SVD) for investigating both the localized and global motions of macromolecules. Results: Configuration space projections from the SVD analysis of a variety of myoglobin simulations are used to characterize the dynamics of the protein. This technique reveals new dynamical motifs, which quantify proposed hierarchical structures of conformational substates for proteins and provide a means by which configuration space sampling efficiency may be probed. The SVD clearly shows that solvent effects facilitate transitions between global conformational substates for myoglobin molecular dynamics simulations. Lyapunov exponents calculated from the configuration space divergence of 15 trajectories agree with previous predictions for the chaotic behavior of complex protein systems, Conclusions: Configuration space projections provide invaluable information about protein motions that would be extremely difficult to obtain otherwise. While the configuration space for myoglobin is quite large, it does have structure. Our analysis of this structure shows that the protein hops between a number of distinct global conformational states, much like,the local behavior observed for an individual residue.

The fourth-order virial coefficients have been calculated exactly to five decimal places for pure fluids of the Lennard-Jones potential at many points in the phase diagram. The calculations were performed through direct evaluation of the integrals, or diagrams, which make up the density expansion of the radial distribution function: included were the standard fast Fourier transform method of evaluating the simply connected diagrams and the evaluation of the bridge diagram for the fourth order in density by expansion in Legendre polynomials. The polynomial-order dependence of the bridge diagram calculation and the range dependence of the simply connected diagrams of the fourth order are found to have more significance than was thought from previous studies, especially in the low-temperature range. This result was confirmed by direct evaluation of the diagrams which construct the virial coefficients, as given by Rowlinson, Barker, and coworkers. This calculation confirmed that numerical convergence has not been achieved at the precision levels previously reported in the literature. These differences, though minor at higher temperatures, can be seen to be more significant at the lower temperature ranges.

Hydration around the DNA fragment d(C5T5) . (A(5)G(5)) is presented from two molecular dynamics simulations of 10 and 12 ns total simulation time. The DNA has been simulated as a flexible molecule with both the CHARMM and AMBER force fields in explicit solvent including counterions and 0.8 M additional NaCl salt. From the previous analysis of the DNA structure B-DNA conformations were found with the AMBER force-field and A-DNA conformations with CHARMM parameters. High-resolution hydration patterns are compared between the two conformations and between C . G and T . A base-pairs from the homopolymeric parts of the simulated sequence. Crystallographic results from a statistical analysis of hydration sites around DNA crystal structures compare very well with the simulation results. Differences between the crystal sites and our data are explained by variations in conformation, sequence, and limitations in the resolution of water sites by crystal diffraction. Hydration layers are defined from radial distribution functions and compared with experimental results. Excellent agreement is found when the measured experimental quantities are compared with the equivalent distribution of water molecules in the first hydration shell. The number of water molecules bound to DNA was found smaller around T . A base-pairs and around A-DNA as compared to B-DNA. This is partially offset by a larger number of water molecules in hydrophobic contact with DNA around T . A base-pairs and around A-DNA. The numbers of water molecules in minor and major grooves have been correlated with helical roll, twist, and inclination angles. The data more fully explain the observed B -> A transition at low humidity. (C) 1999 Academic Press.

The dielectrically consistent reference interaction site model (DRISM) integral equation theory is applied to determine the potential of mean force (PMF) for an alanine tetramer. A stochastic dynamics simulation of the alanine tetramer using this PMF is then compared with an explicit water molecular dynamics simulation, In addition, comparison is also done with simulations using other solvent models like the extended reference interaction site: model (XRISM) theory, constant dielectric and linear distance-dependent dielectric models. The results show that the DRISM method offers a fairly accurate and computationally inexpensive alternative to explicit water simulations for studies on small peptides. (C) 1999 Elsevier Science B.V. All rights reserved.

The structural and dynamical features of the hormone alpha-MSH in solution have been examined over a 100 ns time scale by using free energy molecular mechanics models at room temperature. The free energy surface has been modeled using methods from integral equation theory and the dynamics by the Langevin equation. A modification of the accessible surface area friction drag model was used to calculate the atomic friction coefficients. The molecule shows a stable beta-turn conformation in the message region and a close interaction between the side chains of His(6) Phe(7), and Trp(9). A salt bridge between Glu(5) and Arg(8) was found not to be a preferred interaction, whereas a Glu(5) and Lys(11) salt bridge was not sampled, presumably due to relatively high free energy barriers. The message region was more conformationally rigid than the N-terminal region. Several structural features observed here agree well with experimental results. The conformational features suggest a receptor-hormone interaction model where the hydrophobic side chains of Phe(7) and Trp(9) interact with the transmembrane portion of the MCl receptor. Also, the positively charged side chain of Arg(8) and the imidazole side chain of His(6) may interact with the negatively charged portions of the receptor which may even be on the receptor's extracellular loops. (C) 1999 John Wiley & Sons, Inc.

A conformational search for the most probable structures of the hormone alpha-MSH in aqueous solution was performed in order to help determine the structural features necessary for biological activity. The free-energy surface was modeled using methods from integral equation theory, and high-temperature molecular dynamics was used to enhance conformational sampling. Families of low free-energy structures have been found. The minimum energy structure shows a stable beta-turn conformation in the putative message region that is stabilized by a salt bridge between Glu5 and Lys11. The orientation of the side chains reflects the amphiphilic nature of the peptide, and a close interaction between the side chains of the His6, Phe7 and Trp9 was observed. Several structural features observed in the minimum energy structure agree well with experimental results. The conformational features led to a hypothesis of a receptor-hormone interaction model in which the hydrophobic side chains of Phe7 and Trp9 interact with the transmembrane portion of the human melanocortin (MC1) receptor. Also, the positively charged side chain of Arg8 and the imidazole side chain of His6 may interact with the negatively charged portions of the receptor which may even be on the receptor's extracellular loops.

The grand canonical ensemble techniques-both Monte Carlo and molecular dynamics-have become very popular in recent years, but no direct Link between the number fluctuation results from these simulation methods and a Kirkwood-Buff theory has been established. In this article we look at Kirkwood-Buff integrals computed using thermodynamic averages derived from grand canonical ensemble molecular dynamics simulations and compare them to similar quantities derived from the dielectrically consistent reference interaction site model many-body theory. These calculations will be carried out for three different water models, SPC, SPC/E, and TIP3P. (C) 1999 Academic Press.

The design of a molecular dynamics trajectory database is presented as an example of the organization of large-scale dynamic distributed repositories for scientific data. Large scientific datasets are usually interpreted through reduced data calculated by analysis functions. This allows a database architecture in which the analyzed datasets, that are kept in addition to the raw datasets, are transferred to a database user. A flexible user interface with a well defined Application Program Interface (API) allows for a wide array of analysis functions and the incorporation of user defined functions is a critical part of the database design. An analysis function is executed only when the requested analysis result is not available from an earlier request. A prototype implementation used to gain initial practical experiences with performance and scalability is presented. (C) 1999 Elsevier Science B.V. All rights reserved.

The distribution of sodium and chlorine ions around DNA is presented from two molecular dynamics simulations of the DNA fragment d(C5T5).(A(5)G(5)) in explicit solvent with 0.8 M additional NaCI salt. One simulation was carried out for 10 ns with the CHARMM force field that keeps the DNA structure close to A-DNA, the other for 12 ns with the AMBER force field that preferentially stabilizes B-DNA conformations (Feig and Pettitt, 1998, Biophys. J. 75:134-149). From radial distributions of sodium and chlorine ions a primary ion shell is defined. The ion counts and residence times of ions within this shell are compared between conformations and with experiment. Ordered sodium ion sites were found in minor and major grooves around both A and B-DNA conformations. Changes in the surrounding hydration structure are analyzed and implications for the stabilization of A-DNA and B-DNA conformations are discussed.

Born's simple derivation of the free energy of hydration of ions is classic. It connects the microscopic atomic properties with the macroscopic thermodynamics in a transparent fashion.

Hydration sites are high-density regions in the three-dimensional time-averaged solvent structure in molecular dynamics simulations and diffraction experiments. In a simulation of sperm whale myoglobin, we found 294 such high-density regions. Their positions appear to agree reasonably well with the distributions of waters of hydration found in 38 x-ray and 1 neutron high-resolution structures of this protein. The hydration sites are characterized by an average occupancy and a combination of residence time parameters designed to approximate a distribution of residence times. It appears that although the occupancy and residence times of the majority of sites are rather bulk-like, the residence time distribution is shifted toward the longer components, relative to bulk. The sites with particularly long residence times are located only in the cavities and clefts of the protein. This indicates that other factors, such as hydrogen bonds and hydrophobicity of underlying protein residues, play a lesser role in determining the residence times of the longest-lived sites.

Recent results from molecular dynamics (MD) simulations on hydration of DNA with respect to conformation are reviewed and compared with experimental data. MD simulations of explicit solvent around DNA can now give a derailed model of DNA that not only matches well with the experimental data but provides additional insight beyond current experimental limitations. Such simulation results are analyzed with a focus on differential hydration properties between A- and B-DNA and between C/G and A/T base pairs. The extent of hydration is determined from the number of waters in the primary shell and compared to experimental numbers from different measurements. High-resolution hydration patterns around the whole DNA are shown and correlated with the conformations. The role of ions associating with DNA is discussed with respect to changes in the hydration structure correlating with DNA conformation. (C) 2000 John Wiley & Sons, Inc. Biopoly 38: 199-209, 1998.

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A thermodynamic theory of association to a molecule immobilized near a surface has been developed. Exact equations for the binding enthalpy, entropy and equilibrium reaction constant for an immobilized complex are derived. Using Linear Poisson-Boltzmann theory of the electric double-layer interaction between an ion-penetrable sphere and a hard plate allows a closed form evaluation. We briefly discuss application of the theory to a DNA chip at high (1 M NaCl) and low (0.01 M NaCl) ionic strength for dielectric and metallic substrates. Predicted strong electrostatic effects suggest the feasibility of electronic control of DNA hybridization and design of chips avoiding the DNA folding problem. (C) 2000 Elsevier Science B.V. All rights reserved.

A new boundary condition for computer simulations of interfacial systems is presented. The simulation box used in this boundary condition is the asymmetric unit of space group Pb, and it contains only one interface. Compared to the simulation box using common periodic boundary conditions which contains two interfaces, the number of particles in the simulation is reduced by half. This boundary condition was tested against common periodic boundary conditions in molecular dynamic simulations of liquid water interacting with hydroxylated silica surfaces. It yielded results essentially identical to periodic boundary condition and consumed less CPU time for comparable statistics. (C) 2000 Elsevier Science B.V. All rights reserved.

In the quest to understand both the structural and thermodynamic facets of biomolecular-solvent systems semi-grand canonical ensemble molecular dynamics simulations of a protein in solution are performed. In these simulations only the water molecules in the system are allowed to fluctuate; the final number of water molecules is determined by the chemical potential. An unbiased sampling technique is used for the insertion/deletion procedure of the water molecules thereby providing a benchmark grand ensemble simulation of the hydration structure of proteins. Three different chemical potential simulations were carried out offering a direct route to thermodynamic information from a molecular dynamics simulation. (C) 2000 Elsevier Science B.V. All rights reserved.

Molecular dynamics simulations have been applied to the DNA octamer d(GCGCA-GAAC) (.) d(GTTCGCGC), which has an adenine bulge at the center to determine the pathway for interconversion between the stacked and extended forms. These forms are known to be important in the molecular recognition of bulges. From a total of similar to 35 ns of simulation time with the most recent CHARMM27 force field a variety of distinct conformations and subconformations are found. Stacked and fully looped-out forms are in excellent agreement with experimental data from NMR and x-ray crystallography. Furthermore, in a number of conformations the bulge base associates with the minor groove to varying degrees. Transitions between many of the conformations are observed in the simulations and used to propose a complete transition pathway between the stacked and fully extended conformations. The effect on the surrounding DNA sequence is investigated and biological implications of the accessible conformational space and the suggested transition pathway are discussed, in particular for the interaction of the MS2 replicase operator RNA with its coat protein.

Conformational searches on three closely related pp60(c-src) protein tyrosine kinase inhibitors of varying potencies were performed to determine a structural basis for their activity. The first was a linear peptide (PDNEYAFFQf), the second its 10-membered cyclic analogue, and the third a cyclic analogue with a para carboxyphenylalanine irt place of one the F residues. A common backbone conformation with an antiparallel beta -sheet-like geometry capped by similar beta -turns was found for all three peptides, which may be a binding conformation and gives a candidate pharmacophore for further testing. The interaction between some polar side chains and between some of the aromatic rings may be important for maintaining the correct conformation. The differences in potencies of these inhibitors may be attributed to certain thermodynamic and chemical reasons. (C) 2001 John Wiley & Sons, Inc.

In order to understand the structure of DNAs and their interactions when on microarray surfaces, we performed the first all-atom molecular dynamics simulation of DNA tethered to a surface. On the surface, the binding of the DNA was enhanced, and its average equilibrium conformation was the B form. The DNA duplex spontaneously tilted towards its nearest neighbor and settled in a leaning position with a interaxial distance of 2.2 nm. This close packing of the DNAs, which affects both in situ synthesis and deposition of probes on microarray surfaces, can thus be explained by salted-induced colloidlike DNA-DNA attractions.

In this note, we discuss the application of a methodology combining distributed Lagrange multiplier based fictitious domain techniques, finite-element approximations and operator splitting, to the numerical simulation of the motion of a tripole-like rigid body falling in a Newtonian incompressible viscous fluid. The motion of the body is driven by the hydrodynamical forces and gravity. The numerical simulation shows that the distribution of mass of this rigid body and added moment of inertia compared to a simple cylinder (circular or elliptic) plays a significant role on the particle-fluid interaction. Apparently, for the parameters examined, the action of the moving rigid body on the fluid is stronger than the hydrodynamic forces acting on the rigid body. (C) 2002 Elsevier Science Ltd. All rights reserved.

A simulation study of DPDPE in sodium chloride solution has been poformed and compared with previous simulations using a different interaction potential for the ions. Both global thermodynamics as well as a characterization of association to DPDPE have been calculated. We show that the parameters used for the ions have a profound effect on the association to the peptide in IM NaCl. The observed differences suggest that individual associations in these and previous simulations are sensitive to parameters. (C) 2001 John Wiley & Sons, Inc.

LacI and PurR are highly homologous proteins. Their functional units are homodimers, with ail N-terminal DNA binding domain that comprises the helix-turn-helix (HTH), N-linker, and hinge regions from both monomers, Hinge structural changes are Known to occur upon DNA dissociation but are difficult to monitor experimentally. The initial steps of hinge unfolding were therefore examined using molecular dynamics simulations, utilizing a truncated, chimeric protein comprising the LacI HTH/N-linker and PurR hinge. A terminal Gly-Cys-Gly was added to allow dimerization through disulfide bond formation. Simulations indicate that differences in LacI and PurR hinge primary sequence affect the quaternary structure of the hinge(.)hinge' interface. However, these alternate hinge orientations would be sterically restricted by the core domain. These results prompted detailed comparison of recently available DNA-bound structures for LacI and truncated LacI(1-62) with the PurR structure. Examination revealed that different N-linker and hinge contacts to the core domain of the partner monomer (which binds effector molecule) affect the juxtapositions of the HTH. N-linker, and hinge regions in the DNA binding domain. In addition. the two full-length repressors exhibit significant differences in the interactions between the core and the C-linker connection to the DNA binding domain. Both linkers and the hinge have been implicated in the allosteric response of these repressors. Intriguingly. one functional difference between these two proteins is that they exhibit opposite allosteric response to effector. Simulations and observed structural distinctions are correlated with mutational analysis and sequence information from the LacI/GaIR family to formulate a mechanism for fine-tuning individual repressor function.

Equations for calculating accurate 4-point and 5-point bridge diagrams in terms of h-bonds have been presented and solved for various phase points of the Lennard-Jones fluid. A method of finding a self-consistent solution for the bridge function and the radial distribution function is demonstrated. The significance of this result over bridge diagrams expressed as f-bonds, in terms of its applicability to charged and dipolar models is discussed. Two very simple phenomenological bridge diagram forms for the bridge function for this model are examined and found to give results almost as accurate and in some cases more accurate than previous forms in the literature. This work represents the first use of directly calculated 5-point bridge diagrams in terms of h-bonds, and the many extra orders of f-bond diagrams which they include, in an integral equation result. (C) 2002 American Institute of Physics.

The first two orders of bridge diagrams for the f-bond expansion and the h-bond expansion are calculated for a binary mixture of Lennard-Jones spheres. The method used follows the Legendre polynomial integration methods outlined in the first two papers of this series. As for the pure fluid cases, the thermodynamic results which follow from these methods are found to be in reasonable agreement with the simulation result. Analysis of the thermodynamic and structural results in comparison to the best current bridge function approximations indicate that accurate descriptions of higher order mixtures will require methods beyond the current mean field treatments which are of utility in simple fluids. The methods given are unfortunately not computationally convenient at highest order; however, the lower order diagrams are both accessible and give reasonable numerical results. (C) 2002 American Institute of Physics.

Many theoretical, computational, and experimental techniques recently have been successfully used for description of the solvent distribution around macromolecules. In this Account, we consider recent developments in the areas of protein and nucleic acid solvation and hydration as seen by experiment, theory, and simulations. We find that in most cases not only the general phenomena of solvation but even local hydration patterns are more accurately discussed in the context of water distributions rather than individual molecules of water. While a few localized or high-residency waters are often associated with macromolecules in solution (or crystals from aqueous liquors), these are readily and accurately included in this more general description. The goal of this Account is to review the theoretical models used for the description of the interfacial solvent structure on the border near DNA and protein molecules. In particular, we hope to highlight the progress in this field over the past five years with a focus on comparison of simulation and experimental results.

We present a theoretical thermodynamic framework for the design of more efficient oligonucleotide microarrays. A general thermodynamic relation is derived to describe the electrostatic surface effects on the binding of the assayed biomolecule to a surface-tethered molecular probe. The relation is applied to analyze how the nucleic acid target, the oligonuleotide probe, and their DNA duplex electrostatic interactions with the surface affect the hybridization on DNA arrays. Taking advantage of a closed form exact solution of the linear Poisson-Boltzmann equation for a charged ion penetrable sphere in electrolyte solution interacting with a plane wall, we study the effects of the surface and solution conditions. Binding free energy is found as a function of the surface material, dielectric or metal, the surface charge density, linker molecule length, temperature, and added salt content. The charge or electric potential of the dielectric or metal surface, respectively, is shown to dominate the hybridization, especially at low added salt or short linker length. We predict that substantial enhancement of sensitivity, selectivity, and reliability of microarrays can be achieved by control of the surface conditions. As examples, we discuss how to overcome two limitations of current technologies: nonequal sensitivity of the probes with different GC and AT bases content, and poor match/mismatch discrimination. In addition, we suggest the design of microarray conditions where the tested nucleic acid is unfolded, thus making possible the screening of a larger sequence with single nucleotide resolution. These promising findings are discussed and further experimental tests suggested. (C) 2003 Wiley Periodicals, Inc.

Experiments on DNA microarrays have revealed substantial differences in hybridization thermodynamics between DNA free in solution and surface tethered DNA. Here we develop a mean field model of the Coulomb effects in two-dimensional DNA arrays to understand the binding isotherms and thermal denaturation of the double helix. We find that the electrostatic repulsion of the assayed nucleic acid from the array of DNA probes dominates the binding thermodynamics, and thus causes the Coulomb blockage of the hybridization. The results explain, observed in DNA microarrays, the dramatic decrease of the hybridization efficiency and the thermal denaturation curve broadening as the probe surface density grows. We demonstrate application of the theory for evaluation and optimization of the sensitivity, specificity, and the dynamic range of DNA array devices.

In order to quantify specific ion effects, a simulation study of bis(penicllamine) enkephalin, also known as DPDPE, has been performed in aqueous ammonium chloride solution and has been compared to a previous simulation of DPDPE in aqueous sodium chloride solution. Global thermodynamics have been calculated for a model system and the solution environment around DPDPE has been characterized. Associations of ions with DPDPE have been investigated. The observed differences between sodium chloride solution and ammonium chloride solution suggest that individual cations affect the solvation and peptide binding properties of a given anion. (C) 2002 Wiley Periodicals, Inc.

Recently, many attempts have been made to describe the gene expression temporal dynamics by using systems of differential equations. This is fraught with difficulty, given the current experimental level of understanding. Another way to extract useful information regarding regulation in genetic networks can be provided by our method of Incomplete Modeling using Local Invariants, although at the price of not being able to construct a complete model of the whole system. In this approach we are looking for a set of simple models describing the algebraic or differential relations among just a few variables, genes in this case, which fit the experimental data with the required accuracy. In the present work, we apply this method to gene expression time profiles of 112 genes from rat spinal cord development experiments. We found that many different types of Local Invariants exist in this dataset. Moreover, some isolated self-contained subsystems, whose behavior can be described by closed systems of differential equations, were also found. (C) 2003 Elsevier Inc. All rights reserved.

A structural view of DNA association/hybridization to a target oligonucleotide molecule near a surface has been developed. Recent experiments have showed a kinetically rapid hybridization between large target DNA fragments and oligonucleotides electrostatically immobilized (untethered) to a surface. Theory and computer simulations have been used to investigate the nature of the specificity and affinity in such a system. Simulations were performed for a modified silicon dioxide surface with positively charged groups at neutral pH. The dosing of a surface with unattached oligonucleotide was simulated. The oligonucleotide was found to associate with the surface in salt water in a way that some of the bases remained stacked, and most of the bases near the surface on average pointed preferentially toward the solution, away from the surface. Use of an analytic solution to the linear Poisson-Boltzmann (PB) theory of the electric double layer interaction between DNA and a hard surface predicts tight binding in this system. The simulation thus gives a mechanism for specificity and the theory a mechanism for affinity. The geometry is such that only non-helical base pairs would be accommodated with an irregular backbone.

We present a theoretical model for typical microarray-based single nucleotide polymorphism (SNP) assay of small genomic DNA amount. We derived the adsorption isotherm expressing the on-array hybridization efficiency in terms of genomic target sequence and concentration, oligonucleotide probe sequence and surface density, hybridization buffer, and temperature. This isotherm correctly describes the surface probe density effects, the sensitivity peak, and the melting temperature depression, and is in accord with published experiments. We discuss optimization of parallel SNP genotyping. Our estimates show that SNP detection at a single temperature in aqueous hybridization buffer is restricted by DNA regions that differ by less than 20 that the variety of genotyped SNPs could be substantially, extended using an assay design with high probe density and a large fraction of probes hybridized. (C) 2004 Wiley Periodicals, Inc.

In this paper, we report on the design and analysis of a multilevel method for the solution of the Ornstein-Zernike Equations and related systems of integro-algebraic equations. Our approach is based on an extension of the Atkinson-Brakhage method, with Newton-GMRES used as the coarse mesh solver. We report on several numerical experiments to illustrate the effectiveness of the method. The problems chosen are related to simple short ranged fluids with continuous potentials. Speedups over traditional methods for a given accuracy are reported. The new multilevel method is roughly six times faster than Newton-GMRES and 40 times faster than Picard. (C) 2003 Elsevier Inc. All rights reserved.

It is shown how the leading terms of a semi grand canonical partition function (GCPF) can be used to develop analytic expressions relating activity to concentrations in two-component systems. The simple analytic expressions for activity coefficients can be fitted to activity coefficient versus concentration data for a wide range of aqueous solute systems. Only one or two parameters are required to accurately describe the activity coefficients of nonelectrolyte and electrolyte aqueous solute systems over their entire range of solubility. These forms derive from low-order number expressions of the GCPF that take into account the effective solvent interactions with the solute and between solute molecules for a variable amount of solvent. The GCPF leading terms and fitting parameters define apparent solute-solute oligomerization and solute packing phenomena that increase with solute concentration. Advantages using this grand canonical approach versus previous approaches are discussed.

Motivation: Analysis of statistical properties of DNA sequences is important for evolutional biology as well as for DNA probe and PCR technologies. These technologies, in turn, can be used for organism identification, which implies applications in the diagnosis of infectious diseases, environmental studies, etc. Results: We present results of the correlation analysis of distributions of the presence/absence of short nucleotide subsequences of different length ('n-mers', n = 5 - 20) in more than 1500 microbial and virus genomes, together with five genomes of multicellular organisms (including human). We calculate whether a given n-mer is present or absent (frequency of presence) in a given genome, which is not the usually calculated number of appearances of n-mers in one or more genomes (frequency of appearance). For organisms that are not close relatives of each other, the presence/absence of different 7-20mers in their genomes are not correlated. For close biological relatives, some correlation of the presence of n-mers in this range appears, but is not as strong as expected. Suppressed correlations among the n-mers present in different genomes leads to the possibility of using random sets of n-mers (with appropriately chosen n) to discriminate genomes of different organisms and possibly individual genomes of the same species including human with a low probability of error.

In molecular dynamics the fast multipole method (FMM) is an attractive alternative to Ewald summation for calculating electrostatic interactions due to the operation counts. However when applied to small particle systems and taken to many processors it has a high demand for interprocessor communication. In a distributed memory environment this demand severely limits applicability of the FMM to systems with 0(10 K atoms). We present an algorithm that allows for fine grained overlap of communication and computation, while not sacrificing synchronization and determinism in the equations of motion. The method avoids contention in the communication subsystem making it feasible to use the FMM for smaller systems on larger numbers of processors. Our algorithm also facilitates application of multiple time stepping techniques within the FMM. We present scaling at a reasonably high level of accuracy compared with optimized Ewald methods. (C) 2004 Elsevier Inc. All rights reserved.

The molecular origin of the nonideal behavior for concentrated binary solutions of biochemical compounds is examined. The difference between activities expressed in the molar and molal conventions can be large. Considering the range from dilute to concentrated, we show that molar activity coefficients can be represented by simple but rigorous equations involving between one and three parameters only. We derive a universal relationship interconverting the scales of molarity and molality without requiring the density of the solution. The equations are developed from first principles using a statistical thermodynamic theory of molar activity coefficients. It is shown how to express activity coefficients in different concentration scales, and the advantages and disadvantages of using certain scales are discussed and compared with the experimental data. Several classes of biochemically relevant compounds, many of which are naturally occurring osmolytes, are discussed: six saccharides (glucose, xylose, maltose, mannose, raffinose, and sucrose), four polyols (glycerol, mannitol, erythritol, and sorbitol), five amino acids (glycine, alanine, sarcosine, glycine betaine, and proline), and urea. Of the 16 solutes, 10 could be described in terms of a single parameter that is due to pure first-order effects (packing, hydration, or space limitation). The remaining six exhibit significant second-order effects (solute-solute interactions) and require two additional parameters, one typically identified with the volume occupied per solute molecule in the pure solute (crystal or liquid) and the other with a self-association constant. The activity coefficients of the osmolytes roughly display the rank order found with respect to their ability to stabilize proteins. These findings are discussed in terms of the physical principles that give rise to the activity coefficients.

The hydration behavior of two planar nanoscopic hydrophobic solutes in liquid water at normal temperature and pressure is investigated by calculating the potential of mean force between them at constant pressure as a function of the solute-solvent interaction potential. The importance of the effect of weak attractive interactions between the solute atoms and the solvent on the hydration behavior is clearly demonstrated. We focus on the underlying mechanism behind the contrasting results obtained in various recent experimental and computational studies on water near hydrophobic solutes. The length scale where crossover from a solvent separated state to the contact pair state occurs is shown to depend on the solute sizes as well as on details of the solute-solvent interaction. We find the mechanism for attractive mean forces between the plates is very different depending on the nature of the solute-solvent interaction which has implications for the mechanism of the hydrophobic effect for biomolecules.

Relative hole transfer rates in DNA have been investigated in a number of nucleotide sequences experimentally. Calculation of the transfer rates in DNA is performed relying on the assumption that the transfer is realized as hopping of a hole on guanine sites, each hop being calculated on the basis of superexchange theory. It is shown that the medium reorganization energy and free energy changes play an important role in determining the transfer rate and the type of a nucleotide sequence. The results of the calculations are compared with experimental data covering a range of available sequences. (C) 2004 Elsevier B.V. All rights reserved.

We describe the model dynamical behavior of the solvent between two nanoscopic hydrophobic solutes. The dynamics of the vicinal water in various sized traps is found to be significantly different from bulk behavior. We consider the dynamics at normal temperature and pressure at three intersolute distances corresponding to the three solvent separated minima in the free energy profile between the solutes with attractions. These three states correspond to one, two, and three intervening layers of water molecules. Results are obtained from a molecular dynamics simulation at constant temperature and pressure (NPT) ensemble. Translational diffusion of water molecules trapped between the two solutes has been analyzed from the velocity correlation function as well as from the mean square displacement of the water molecules. The rotational behavior has been analyzed through the reorientational dynamics of the dipole moment vector of the water molecule by calculating both first and second rank dipole-dipole correlation functions. Both the translational and reorientational mobilities of water are found to be much slower at the smaller separation and increases as the separation between solutes becomes larger. The occupation time distribution functions calculated from the trajectories also show that the relaxation is much slower for the smallest intersolute separation as compared to other wider separations. The sublinear trend in mean square displacement and the stretched exponential decay of the relaxation of dipolar correlation and occupation distribution function indicate that the dynamical behavior of water in the confined region between two large hydrophobic solutes departs from usual Brownian behavior. This behavior is reminiscent of the behavior of water in the vicinity of protein surface clefts or trapped between two domains of a protein.

We employ constant pressure molecular dynamics simulations to investigate the effects of solute size and solute-water dispersion interactions on the solvation behavior of nanoscopic hydrophobic model solutes in water at normal temperature and pressure. The hydration behavior around a single planar atomic model solute as well as a pair of such solutes have been considered. The hydration water structure of a model nanoscopic solute with standard Lennard-Jones interaction is shown to be significantly different from that of their purely repulsive analogues. The density of water in the first solvation shell of a Lennard-Jones solute is much higher than that of bulk water and it remains almost unchanged with the increase of the solute dimensions from one to a few nanometers. On the other hand, for a purely repulsive analogue of the above model, solute hydration behavior shows a marked solute size dependence. The contact density of water in this case decreases with the increasing dimension of the solute. We also demonstrate the effect of solute-solvent attraction on the cavity formation in the inter solute region between two solutes with an inter solute separation of 6.8 angstrom, corresponding to the first solvent separated minimum in the free energy profile as obtained in our earlier work.

We present a new load balanced parallel implementation of a non-adaptive version of Greengard and Rokhlin's fast multipole method for distributed memory architectures with focus on applications in molecular dynamics. We introduce a novel load balancing and communication overlapping scheme. Our implementation includes periodic boundary conditions calculations and facilitates multiple time stepping techniques without sacrificing determinism of computation and scales to hundreds of processor for systems of only O (10k) atoms. (c) 2005 Elsevier Inc. All rights reserved.

The monomer and dimer of the bacterium Serratia marcescens endonuclease (SMnase) are each catalytically active and the two subunits of the dimer function independently of each other. Specific interfacial waters may play a role in stability, complex formation, and functionality. We performed molecular dynamics simulations of both a subunit of SMnase and its model built complex with DNA and analyzed the relation of the hydration sites to the catalytic mechanism. It was found that the binding of DNA has little influence on the global hydration properties of the protein, including occupancy and water residence time distributions. DNA and protein recognition in our model mainly involves direct contacts by hydrogen bond and hydrophobic interactions. Water-mediated contacts exist, but are less common. Three interior water clusters were identified for SMnase. One cluster around the active site in the monomer-DNA complex shows relatively strong interactions between hydration sites as well as between the sites and the biomolecules. The simulated cluster properties agreed well with experimental data. The magnesium ion shows ligand exchange. Although Mg2+ keeps six ligands during the entire simulation, upon the binding of DNA, Asn119 loses its coordination with Mg2+, while one nonbridging oxygen of the phosphate of a DNA residue and two oxygen atoms of the side chain of Glu127 become the ligands. Waters in a nearby cluster exchange and participate in the resolvation of groups in the presence of DNA. Water thus not only participates in the cleavage of DNA but also can stabilize the transition state and the leaving groups in our model.

An understanding of the impact of the crowded conditions in the cytoplasm on its biomolecules is of clear importance to biochemical, medical, and pharmaceutical science. Our previous work on the use of small biochemical compounds to crowd protein solutions indicates that a quantitative description of their nonideal behavior is possible and straightforward. Here, we show the structural origin of the nonideal solution behavior. We discuss the consequences of these findings regarding protein folding stability and solvation in crowded solutions through a structural analysis of the m-value or the change in free-energy difference of a macromolecule in solution with respect to the concentration of a third component.

Two complementary routes to a new integral equation theory for site-site molecular fluids are presented. First, a simple approximation to a subset of the atomic site bridge functions in the diagrammatically proper integral equation theory is presented. This in turn leads to a form analogous to the reactive fluid theory, in which the normalization of the intramolecular distribution function and the value of the off-diagonal elements in the density matrix of the proper integral equations are the means of propagating the bridge function approximation. Second, a derivation from a topological expansion of a model for the single-site activity followed by a topological reduction and low-order truncation is given. This leads to an approximate numerical value for the new density coefficient. The resulting equations give a substantial improvement over the standard construction as shown with a series of simple diatomic model calculations. (c) 2005 American Institute of Physics.

Type II topoisomerases resolve problematic DNA topologies such as knots, catenanes, and supercoils that arise as a consequence of DNA replication and recombination. Failure to remove problematic DNA topologies prohibits cell division and can result in cell death or genetic mutation. Such catastrophic consequences make topoisomerases an effective target for antibiotics and anticancer agents. Despite their biological and clinical importance, little is understood about how a topoisomerase differentiates DNA topologies in a molecule that is significantly larger than the topoisomerase itself. It has been proposed that type II topoisomerases recognize angle and curvature between two DNA helices characteristic of knotted and catenated DNA to account for the enzyme’s preference to unlink instead of link DNA. Here we consider the electrostatic potential of DNA juxtapositions to determine the possibility of juxtapositions occurring through Brownian diffusion. We found that despite the large negative electrostatic potential formed between two juxtaposed DNA helices, a bulk counterion concentration as small as 50 mM provides sufficient electrostatic screening to prohibit significant interaction beyond an interhelical separation of 3 nm in both hooked and free juxtapositions. This suggests that instead of electrostatics, mechanical forces such as those occurring in anaphase, knots, catenanes, or the writhe of supercoiled DNA may be responsible for the formation of DNA juxtapositions.

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