Our work is primarily concerned with the structure, dynamics and thermodynamics of peptides, proteins and nucleic acids. An area of particular concern is the effects of solvation and hydration on the properties of biological molecules. There are two major parts to the protein (or nucleic acid) folding problem: the search and the work surface. Without the solvent effects we have only a gas phase energy surface which is not representative of the solution state. In this lab we are working to understand the solvationproperties of these molecules.

Our series of efforts in the area of the conformational properties of peptides and small biological molecules in aqueous solution has progressed in both fundamental and practical (applied) aspects. The work on peptides and peptide analogs in particular is aided by close relations with several experimental groups (both synthetic and biological). A computational study of the effects of salt on the structure and dynamics of the bis-penicillamine enkephalin has led to the beginnings of a molecular view of the Hofmeister (lyotropic) series for salting peptides in and out of solution. This is in some ways the inverse of the protein/peptide folding problem and therefore has ramifications for protein/peptide design. The success from this work has provided us with the opportunity to now expand the efforts to explore a number of different effects related to the Hofmeister series.

Many of the studies done in this laboratory are computational in nature and require large scale computing resources. However, considerable progress has been made toward new theory for the structure of biological molecules saline solutions. The thermally accessible conformations of these molecules, and the distribution of these conformations, are central to understanding their activity. This fundamental information is especially important for the design of new drugs with increased potency, lifetime or both. This work has yielded methods to rationalize and predict conformationally constrained analogs in short peptide sequences. Several molecules have now yielded to this method originally tested on the opioid peptides. Recently, the immune response activating peptide Tuftsin and analogs were considered and possible super potent analogs proposed. The spectacular success of that work in not only explaining the experimental (nmr) structural data but yielding compounds which are now in trials has led to a resurgence in experimental work concerning this part of the immune system.

We recently presented a new view of the solvation of proteins that goes beyond the accessible surface area picture to include fluctuations of the protein and the surrounding solution. This theory of protein solvent penetration has not only changed our concepts about solvents role in protein structure but has also yielded a new technique for solvent refinement of x-ray diffraction data. This now allows the use of the so called low resolution data in the refinement of the protein atom positions and thus a better representation of solvent is leading to a clearer picture of the proteins themselves.

These ideas and techniques are now being extended to conformational problems in saline solution for nucleic acids. Triple helices of DNA have recently come under considerable scrutiny. Early studies showed that single stranded oligonucleotides could be used to inhibit gene transcription in vitro as opposed to inhibition of translation or antisense approaches. Expanding on this observation, to target any random base sequence in a promoter region, requires a thorough understanding of the microscopic reasons for stability in these systems. While nmr experiments have yielded some data no complete (3-d) atomic resolution structure of triple helices exists todate. To this end we have performed theoretical, modeling and computer simulation studies of a triple helix in explicit aqueous salt solution. We found patterns of water associations specific to certain sequences of triple helical DNA. These structures are not present in duplex DNA nor in other known less stable triple helical structures. We have found a new spine of hydration unrelated to the one in the minor groove of TA rich double helices in the B-form. This unique hydration structure is located in the groove formed between the first and third stands of a CGG triplex. These waters of hydration are thought to play an important role in stabilizing G-rich antiparallel triple helices at neutral to physiological pH. While such G-rich structures have been the basis of in vivo investigations todate, the ability to target any random sequence with appropriate specificity and stability remains elusive. We are studying the characteristics of nonnatural triplex forming oligonucleotide bases recognizing other sequences in double helical DNA. The calculations so far indicate that certain nonnatural bases should bind more specifically and strongly to the duplex than the natural bases.

We are also interested in the fusion of informatics and physics. How one gets from Biophysics to Bioinformatics is a challenge at present. New tools and concepts in complexity theory as well as effcient algorithms are required. We have discovered a number of features of whole genomes which allow us to use the tools of statistical distribution functions to understand the information (and randomness) of genomes.

"Theoretical and Experimental Studies of Salt-Peptide Solutions", Adv. Comput. Biology, 1, 231-248 (1994); Gail E. Marlow and B.M. Pettitt.

"The Relationship Between Mutation Rates for the (C.G) to (T.A) Transition and Features of T.G Mispair Structures in Different Neighbor Environments", Determined by Free Energy Molecular Mechanics, Nucleic Acids Research, 21 6028-6037 (1994); Rahul Mitra, B.M. Pettitt, Graciela Ram'e and R.D. Blake.

"A Connected-Cluster of Hydration around Myoglobin: Correlation between Molecular Dynamics Simulations and Experiment", Proteins: Structure, Function and Genetics, bf 18 133-147 (1994); Val`ere Lounnas and B. M. Pettitt.

"A Global Model of the Protein-Solvent Interface", Biophysical J., 66, 601-614 (1994); Val`ere Lounnas, B. M. Pettitt and George N. Phillips.

"Peptide Conformations Are Restricted by Solution Stability, J. Phys. Chem, 99 1-2 (1995); John Perkyns and B.M. Pettitt.

"Water Around Myoglobin, Protein Science 4, 149-158 (1995); George N. Phillips and B.M. Pettitt.

"Nanosecond Dynamics and Structure of a model DNA Triple Helix in Saltwater Solution, J. Am. Chem. Soc. 117 2147- 2158 (1995); S. Weerasinghe, P. Smith, V. Mohan, Y.-K. Cheng, B.M. Pettitt.

"Conformational States Governing the Rates of Spontaneous Transition Mutations, Biopolymers 36 169-180 (1995); Rahul Mitra, B. M. Pettitt, and R. D. Blake.

"A Sampling Problem in Molecular Dynamics Simulations of Macromolecules, Proc. Nat. Acad. Sci. USA 92 3288-92 (1995); James B. Clarage, Tod Romo, B. Kim Andrews, B. M. Pettitt and George N. Phillips Jr.

"Dielectric Response of Triplex DNA in Ionic Solution from Simulations" Biophys. J. 69 1519-1527 (1995); L. Yang, S. Weerasinghe, P. Smith and B.M. Pettitt.

"Simulations of Conformations of Tuftsin and Cyclic Tuftsin Analogs, Int. J. Pep. Prot. Res. 46 372-380 (1995); C.V. Valdeavella, H. Blatt and B.M. Pettitt.

"B to A transition of DNA on the Nanosecond Timescale," J. Phys. Chem 100, 2564-2566 (1996); L. Yang and B. Montgomery Pettitt.

" Salting in Peptides: Conformationally dependent solubilities and phase behavior of a tripeptide zwitterion in electrolyte solution," J. Am. Chem. Soc. 118, 1164-1172 (1996); John Perkyns, Y. Wang and B.M. Pettitt.

"Structure and Stability of a Model Pyrimidine-Purine-Purine DNA Triple Helix with a GC.T Mismatch by Simulation," Biochem. 34 16269-16278 (1996); S. Weerasinghe, P.E. Smith and B.M. Pettitt.

"Tuftsin and Tuftsin Analogs: Biology, Synthesis and Design Theory," Curr. Med. Chem. 3 153--166 (1996); Kenji Nishioka, John McMurray, Fahad Al Obeidi and B.M. Pettitt. "Salt effects on peptide conformers: A dielectric study of tuftsin," Biophysical J. 71 3022-3029 (1996); L. Yang, C.V. Valdeavella, H.D. Blatt and B. M. Pettitt.

"Modeling the DNA solvent Interface," Biopolymers 41 107-119 (1997); W. Rudnicki and B. M. Pettitt.

"A Simple Two Dimensional Representation for the Common Secondary Structural Elements of Polypeptides and Proteins," Proteins: Structure, Function and Genetics 27:227-234 (1997); Paul Smith, Herb Blatt and B. M. Pettitt.

"Environmentally Dependent Conformational Preferences of Peptides," J. Am. Chem. Soc. 119 8714-8715 (1997); Paul Smith, Herb Blatt and B. M. Pettitt.

"Experiment vs. Force Fields: DNA conformation from Molecular Dynamics Simulation," J. Phys. Chem. 101 7361-7363 (1997); Michael Feig and B. M. Pettitt.

"Protonation effects on the Equilibrium and Dynamical Properties of the Alanine Tetrapeptide," J. Phys. Chem. 101 7628-7634 (1997); Herb Blatt, Paul Smith, and B. M. Pettitt.

" Structural Equilibrium of DNA Represented with Different Force Fields," Biophys. J. 75 (1998); Michael Feig and B. M. Pettitt.

"Comparison of Simulated and Experimentally Determined Dynamics for a Variant of the LacI DNA-Binding Domain, Nlac-P," Biophysical J. 74 413-421 (1998); Liskin Swint-Kruse, K.S. Matthews, P.E. Smith, and B. M. Pettitt.

"NMR and Quenched Molecular Dynamics Studies of Superpotent Linear and Cyclic alpha-Melanotropins", Int. J. Pep. Prot. Res. 51 420-431 (1998); F. Al-Obeidi, S. O'Connor, Constantin Job, V.J. Hruby and B. M. Pettitt.

"Reconstructing the Protein-Water Interface," Biopolymers 45 469-478 (1998); Vladimir Makarov, K.A. Andrews, and B. M. Pettitt.

"Protein Hydration Density: Theory, Simulation and Crystallography," Curr. Op. Struct. Bio. 8 218-221 (1998); Vladimir Makarov, K.A. Andrews, and B. M. Pettitt.

"Diffusion of Solvent around Biomolecular Solutes: a Molecular Dynamics SImulation Study," Biophysical J. 75 1-9 (1998); Vladimir Makarov, M. Feig, K.A. Andrews, and B. M. Pettitt.

"Characterizing Global Substates of Myoglobin" Structure 6 587-594 (1998); B. Kim Andrews, Tod Romo, James B. Clarage, B. M. Pettitt and George N. Phillips Jr.

"Crystallographic Water Sites from a Theoretical Perspective" Structure, 6 1351-1354 (1998); M. Feig and B. M. Pettitt.

"Modeling Consistent with Experiment: High resolution Hydration patterns in Correlation with DNA Sequence and Conformation," Journal of Molecular Biology (1999); M. Feig and B. M. Pettitt.

"Comparison of the Potentials of Mean Force for Alanine Tetrapeptide between Integral Equation Theory and Simulation" Biophysical Chemistry (1999); N. Prabhu, J. Perkyns, H. Blatt, P. Smith and B.M. Pettitt.

"Structure and Dynamics of alpha-MSH using DRISM Integral Equation theory and Stochastic Dynamics" Biopolymers, (1999); N.V. Prabhu, J.S. Perkyns and B. M. Pettitt.

"Modeling of alpha-MSH conformations with implicit solvent" Journal of Peptide Research, 54 394-407 (1999); N.V. Prabhu, J.S. Perkyns and B.M. Pettitt.

"Sodium and Chlorine Ions as Part of the DNA Solvation Shell " Biophysical J. 77 1769-1781 (1999); Michael Feig, B. M. Pettitt.

"Residence times of water molecules in the hydration sites of myoglobin" Biophysical J. 79 2966-2974 (2000); V. Makarov, K. Andrews, P. Smith, and B. M. Pettitt .

"A Molecular Simulation Picture of DNA Hydration around A- and B-DNA" Biopolymers 48 199-209 1998:(2000); Michael Feig and B. M. Pettitt.

"Conformations of an Adenine Bulge in a DNA Octamer and its Influence on DNA Structure from a Molecular Dynamics Simulation", Biophys. J. 81 352 - 370 (2001); Michael Feig, Martin Zacharias and B. M. Pettitt.

"Structural Basis for the Activity of pp60c-src Protein Tyrosine Kinase Inhibitors" Biopolymers, 59 167-179 (2001); N.V. Prabhu, S.A. Siddiqui, J.S. McMurray and B. M. Pettitt.

"Semi grand canonical ensemble molecular dynamics simulation of BPTI" Chem. Phys. 258 405-413 (2000); G. Lynch and B.M. Pettitt.

"Spontaneous Formation of Structures on the Surface of DNA microarrays by an All-atom Molecular Dyanmics Simulation" Theo. Chem. Accounts (2001); Ka-Yiu Wong and B.M. Pettitt.

"Simulations of the Bis-Penicillamine Enkephalin in Sodium Chloride Solution: A Parameter Study" Biopolyymers 60 134-152 (2001); Gail Marlow and B. M. Pettitt

"Fine tuning function: Correlation of hinge domain interactions with functional distinctions between LacI and PurR" Protein Science 11 778-794 (2002); Liskin Swint- Kruse, C. Larson, B. M. Pettitt and K.S. Matthews.

"Solvation and Hydration of Proteins and Nucleic acids: a Theoretical View of Simulation and Experiment" Accounts of Chemical Res. 35 376- 384 (2002); V. Makarov, B.M. Pettitt and M. Feig.

"Surface Electrostatic Efects in Oligonucleotide Microarrays: Control and Optimization of Binding Thermodynamics" Biopolymers (in press); A. Vainrub and B.M. Pettitt.

"Coulomb Blockage of Hybridization in Two-Dimensional DNA Arrays" Phys. Rev. E 66, 41905 (2002); A. Vainrub and B.M. Pettitt.

"Simulation of the Bis-Penicillamine Enkephalin in Ammonium Chloride Solution:a comparison with Sodium Chloride" Biopolymers (2003); Gail E. Marlow and B. M. Pettitt.

"Theoretical Considerations for the E±cient Design of DNA Arrays", in Biomedical Technology and Devices Handbook, Eds. James E. Moore Jr. and George Zouri- dakis CRC Press,14:1-12, 2003; Arnold Vainrub, Tong Bin Li, Yuriy Fofanov and B. M. Pettitt.

"Reconstruction of the genetic regulatory dynamics of the Rat spinal cord devel- opment: Local Invariants Approach" J. Biomed. Informatics 35 343-351(2003); Y. Fofanov and B.M. Pettitt.

"A non-Watson-Crick Motif of Base-pairing On Surfaces for Untethered Oligonucleotides", Molecular Simulation 30, 121-129 (2004); Ka-Yiu Wong, Arnold Vainrub, Tom Powdrill, Michael Hogan, and B. M. Pettitt.

"Microscopic DNA Fluctuations are in accord with macroscopic DNA stretching elas- ticity without strong dependence on force field choice" NATO ASI Series: Metal Ligand Interactions Kluwer Academic Press, ed. N. Russo 193-204 (2003); John Marko, Michael Feig and B. M. Pettitt.

"Sensitive Quantitative Nucleic Acid Detection Using Oligonucleotide Microarrays", J. Am. Chem. Soc., 125, 7798-7799 (2003); Arnold Vainrub and B. M. Pettitt.

"Orientation of DNA on a surface from simulation", Biopolymers, 73, 570-578 (2004); Ka-Yiu Wong and B. M. Pettitt.

"Theoretical aspects of genomic variation screening using DNA microarrays", Biopolymers 73, 614-620 (2004); Arnold Vainrub and B. M. Pettitt.

"How correlated (independent) are appearances of n-mers in di®erent genomes?" Bioinformatics (in press); Yi Luo, Charles Katili, Jim Wang, Yuri Y. Belosludtsev, Thomas F. Powdrill, Viacheslav Fofanov, Sergey Chumakov, Yuriy Fofanov, and B. M. Pettitt.

"Short subsequences in genomes: How random are they?" Technical Report, Comp. Sci. U of H (2004); Yi Luo, Charles Katili, Jim Wang, Yuri Y. Belosludtsev, Thomas F. Powdrill, Viacheslav Fofanov, Sergey Chumakov, Yuriy Fofanov, and B. M. Pettitt.

"Uncovering the basis of non-ideal behavior of biological molecules", Biochemistry 43(45), 14472-14484 (2004); Joerg Roesgen, B. M. Pettitt, David Wayne Bolen.

"Using Statistical Properties of Short Subsequences in Microbial Identification", Proc. Int. Con. Math. Eng. Tech. Med. Bio. Sci. S. Chumakov, Catherine Putonti, B. M. Pettitt, George E. Fox, Richard C. Willson, Yuriy Fofanov, (Las Vegas, Nevada), 2004: 363-367.

"Combined hopping-super exchange model of a hole transfer in DNA" Chem. Phys. Lett. 400(1-3), 47-53 (2004); V. D. Lakhno, V. B. Sultanas, B.M. Pettitt.

"DNA Saline Solutions Near Surfaces: Design Parameters of DNA Arrays" NATO Sci- ence Series Kluwer Academic Press, ed. D Henderson, M. Holovko and A. Trokhymchuk 206, 381{393 (2005); B.M. Pettitt, Arnold Vainrub, and Ka-Yiu Wong.

"Solvent Participation in Serratia marcescens Endonuclease Complexes" Proteins: Structure, Function, Bioinformatics 62(4) 982-995 (2006); Chuanying Chen, Brian W. Beck, Kurt Krause and B.M. Pettitt.

"Protein Folding, Stability and Solvation Structure in Osmolal Solutions" Biophys. J. 89, 29882997 (2005); Joerg Roesgen, B. M. Pettitt, David Wayne Bolen.

"Electrostatics of DNA-DNA juxtapositions: Consequences for type II topoisomerase function" J. Phys. Cond. Matter, 18(14), S173-S185 (2006); Graham L. Randall, B. M. Pettitt, Gregory R. Buck, E. Lynn Zechiedrich.

"The theoretical basis of universal identification systems for bacteria and viruses", The Journal of Biological Physics and Chemistry 5, 121-11128 (2005); S. Chumakov, C. Belapurkar, C. Putonti, T.-B. Li, B.M. Pettitt, G. E. Fox, R. C. Willson and Y. Fofanov.

"Using Mutual Information to Discover Temporal Patterns in Gene Expression Data", Medical Physics: Ninth Mexican Symposium on Medical Physics, 854 25-30 (2006); Chumakov S., Ballesteros E., Snchez Rodrguez, J.E., Chvez, A., Zhang, M., Pettitt, B.M. and Fofanov, Y.

"An Analysis of the Molecular Origin of Osmolyte-dependent Protein Stability" Prot. Sci. 16, 733-743 (2007); Joerg Roesgen, B. M. Pettitt, David Wayne Bolen.

"The Effects of Dimerization of Serratia marcescens Endonuclease on Water Dynamics", Biopolymers 85(3), 241-252 (2007); Chuanying Chen, Brian W. Beck, Kurt Krause, Tiffany E. Weksberg and B.M. Pettitt.

"The Dewetting transition and the Hydrophobic Effect" Journal of the American Chemical Society, 129(15), 4848-4852 (2007); Niharendu Choudhury and B.M. Pettitt.

"Preferential Solvation in Urea Solutions at Different Concentrations: Properties from Simulation Studies" J. Phys. Chem. 111(19), 5233-5242 (2007); H. Kokubo and B. M. Pettitt.

"Molecular Dynamics Simulations of Trichomonas vaginalis Ferredoxin: Loop-Cap Transition May Explain Selective Activation of Metronidazole" Biophys. J. 92, 3337- 3345 (2007); Tiffany E Warth, Gillian C Lynch, Kurt L Krause, B.M. Pettitt.

"PIDA: A new algorithm for pattern identification", O. J. Bioinf. (in press) Catherine Putonti, B. M. Pettitt, Jeffrey Reid and Yuriy Fofanov.

"Molecular basis of the near ideality of urea solutions" Biophysical J. 93, 3392-3407 (2007); H. Kokubo, Joerg Roesgen, David Wayne Bolen and B.M. Pettitt.

"Peptide conformations of a microarray surface-tethered epitope of the tumor suppres- sor p53" J. Phys. Chem. , 111(49), 13797-13806 (2007); Jun Feng, Ka-Yiu Wong, Gillian Lynch, Xiaolian Gao and B.M. Pettitt.

"Free Energy Calculations for DNA near surfaces using an Ellipsoidal Geometry", Comm. Phys. Comm. 3, 1117-1131 (2008); J. Ambia-Garrido, and B.M. Pettitt

"Determination of the transition-state entropy for aggregation suggests how the growth of sickle cell hemoglobin polymers can be slowed", J. Mol. Biol. (2008); Peter G Vekilov, Nihar Choudhury, B.M. Pettitt, Ronald L Nagel