Advertisement

Computer Simulation of Protein-Ligand Interactions

Challenges and Applications
  • Sergio A. Hassan
  • Luis Gracia
  • Geetha Vasudevan
  • Peter J. Steinbach
Part of the Methods in Molecular Biology™ book series (MIMB, volume 305)

Abstract

The accurate modeling of protein-ligand interactions, like any prediction of macromolecular structure, requires an energy function of sufficient detail to account for all relevant interactions and a conformational search method that can reliably find the energetically favorable conformations of a heterogeneous system. Both of these prerequisites represent daunting challenges. Consequently, the routine docking of small molecules or peptides to proteins in their correct binding modes, and the reliable ranking of binding affinities remain unsolved problems. Nonetheless, computational techniques are continually evolving so as to broaden the range of feasible applications, and the accuracy of predictions and theoretical approaches can often be of great help in guiding and interpreting experiments. We discuss the energetics of protein-ligand systems and survey conformational searching techniques. We illustrate how molecular modeling of a protein-ligand complex sheds light on the observed resistance of a mutant dihydrofolate reductase to the antibiotic trimethoprim. In another example, we show that relaxation of side chains in different crystal structures of the same complex, benzamidine bound to trypsin, is needed to draw sensible conclusions from the calculations. The results of these relatively simple conformational searches underscore the importance of incorporating protein flexibility in simulations of protein-ligand interactions, even in the context of relatively rigid binding pockets.

Key Words

Molecular mechanics molecular dynamics Monte Carlo simulation conformational searching protein-ligand interaction implicit solvent free energy binding affinity 

References

  1. 1.
    Schneidman-Duhovny D., Nussinov R., and Wolfson H. J. (2004) Predicting molecular interactions in silico: II. Protein-protein and protein-drug docking. Curr. Med. Chem. 11(1), 91–107.PubMedGoogle Scholar
  2. 2.
    Brooijmans N. and Kuntz I. D. (2003) Molecular recognition and docking algorithms. Annu. Rev. Biophys. Biomol. Struct. 32, 335–373.PubMedGoogle Scholar
  3. 3.
    Taylor R. D., Jewsbury P. J., and Essex J. W. (2002) A review of protein-small molecule docking methods. J. Comp. Aid. Mol. Des. 16(3), 151–166.Google Scholar
  4. 4.
    Lengauer T. and Rarey M. (1996) Computational methods for biomolecular docking. Curr. Op. Struct. Biol. 6(3), 402–406.Google Scholar
  5. 5.
    Perez C. and Ortiz A. R. (2001) Evaluation of docking functions for protein-Ligand docking. J. Med. Chem. 44, 3768.PubMedGoogle Scholar
  6. 6.
    Roche O., Kiyama R., and Brooks C. L. (2001) Ligand-Protein database: linking protein-ligand complex structures to binding data. J. Med. Chem. 44(22), 3592–3598.Google Scholar
  7. 7.
    Rarey M. and Lengauer T. (2000) A recursive algorithm for efficient combinatorial library docking. Perspect. Drug Discov. Des. 20(1), 63–81.Google Scholar
  8. 8.
    Morelli X., Dolla A., Czjzek M., Palma P. N., Blasco F., Krippahl L., Moura J. J. G., and Guerlesquin F. (2000) Heteronuclear NMR and soft docking: an experimental approach for a structural model of the cytochrome c(553)-ferre-doxin complex. Biochemistry 39, 2530–2537.PubMedGoogle Scholar
  9. 9.
    Hoffmann D., Kramer B., Washio T., Steinmetzer T., Rarey M., and Lengauer T. (1999) Two-stage method for protein-ligand docking. J. Med. Chem. 42(21), 4422–4433.PubMedGoogle Scholar
  10. 10.
    Budin N., Majeux N., Tenette-Souaille C., and Caflisch A. (2001) Structure-based ligand design by a build-up approach and genetic algorithm search in conformational space. J. Comp. Chem. 22, 1956–1970.Google Scholar
  11. 11.
    Thormann M. and Pons M. (2001) Massive docking of flexible ligands using environmental niches in parallelized genetic algorithms. J. Comp. Chem. 22, 1971–1982.Google Scholar
  12. 12.
    Majeux N., Scarsi M., Apostolakis J., Ehrhardt C., and Caflisch A. (1999) Exhaustive docking of molecular fragments with electrostatic solvation. Proteins 37, 88–105.PubMedGoogle Scholar
  13. 13.
    Teng M. K., Smolyar A., Tse A. G., Liu J. H., Liu J., Hussey R. E., Nathenson S. G., Chang H. C., Reinherz E. L., and Wang J. H. (1998) Identification of a common docking topology with substantial variation among different TCR-pep-tide-MHC complexes. Curr. Biol. 8, 409-12.Google Scholar
  14. 14.
    Shoichet B. K., Leach A. R., and Kuntz I. D. (1999) Ligand solvation in molecular docking. Proteins 34,4–16.PubMedGoogle Scholar
  15. 15.
    Schafferhans A. and Klebe G. (2001) Docking ligands onto binding site representations derived from proteins built by homology modelling. J. Mol. Biol. 307, 407–427.PubMedGoogle Scholar
  16. 16.
    Sandak B., Wolfson H. J., and Nussinov R. (1998) Flexible docking allowing induced fit in proteins: insights from an open to closed conformational isomers. Proteins 32, 159–174.PubMedGoogle Scholar
  17. 17.
    Makino S. and Kuntz I. D. (1997) Automated flexible ligand docking method and its application for databese search. J. Comp. Chem. 18, 1812–1825.Google Scholar
  18. 18.
    Lybrand T. P. (1995) Ligand-protein docking and rational drug design. Curr. Opin. Struct. Biol. 5, 224–228.PubMedGoogle Scholar
  19. 19.
    Lorber D. M. and Shoichet B. K. (1998) Flexible ligand docking using conformational ensembles. Protein Sci. 7, 938–950.PubMedGoogle Scholar
  20. 20.
    Mandell J. G., Roberts V. A., Pique M. E., Kotlovyi V., Mitchell J. C., Nelson E., Tsigelny I., and Ten Eyck L. F. (2001) Protein docking using continuum electrostatics and geometric fit. Protein Eng. 14, 105–113.PubMedGoogle Scholar
  21. 21.
    Pathria R. K. (1972) Statistical Mechanics. International Series in Natural Philosophy. Vol. 45. Pergamon Press.Google Scholar
  22. 22.
    McQuarrie D. A.(1976) Statistical Mechanics. Harper & Row, New York, NY.Google Scholar
  23. 23.
    Hill T. L. (1986) An Introduction to Statistical Thermodynamics. Dover, New York, NY.Google Scholar
  24. 24.
    Bruce Yu Y., Privalov P. L., and Hodges R. S. (2001) Contribution of translational and rotational motions to molecular association in aqueous solution. Biophys. J. 81, 1632–1642.Google Scholar
  25. 25.
    Siebert X. and Amzel L. M. (2004) Loss of translational entropy in molecular associations. Proteins 54, 104–115.PubMedGoogle Scholar
  26. 26.
    Bohm H. J. (1994) The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. J. Comp. Aid. Mol. Des. 8, 243–256.Google Scholar
  27. 27.
    Meng C., Shoichet B. K., and Kuntz I. D. (1992) Automated docking with grid-based energy evaluation. J. Comp. Chem. 13, 505–524.Google Scholar
  28. 28.
    Eldridge M. D., Murray C. W., Auton T. R., Paolinine G. V., and Mee R. P. (1997) Empirical scoring functions.1. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J. Comp. Aid. Mol. Des. 11, 425–445.Google Scholar
  29. 29.
    Muegge I. and Martin Y. C. (1999) A general and fast scoring function for protein-ligand interactions: A simplified potential approach. J. Med. Chem. 42, 791–804.PubMedGoogle Scholar
  30. 30.
    Jones G., Willett P., and Glen R. C. (1995) Molecular recognition of receptor-sites using a genetic algorithm with a description of solvation. J. Mol. Biol. 245, 43–53.PubMedGoogle Scholar
  31. 31.
    Rarey M., Kramer B., Lengauer T., and Klebe G. (1996) A fast flexible docking method using an incremental construction algorithm. J. Mol. Biol. 261, 470–489.PubMedGoogle Scholar
  32. 32.
    Gilson M. K., Given J. A., Bush B. L., and McCammon J. A. (1997) The statistical-thermodynamic basis for computation of binding affinities: A Critical Review. Biophys. J. 72, 1047–1069.PubMedGoogle Scholar
  33. 33.
    Singh U. C., Brown F. K., Bash P. A., and Kollman P. A. (1987) An approach to the application of free-energy perturbation-methods using molecular-dynamics-applications to the transformations of Ch3oh-Ch3ch3, H3o+- Nh4+, gly-cine-alanine, and alanine-phenylalanine in aqueous-solution and to H3o+ (H2o)3-Nh4+(H2o)3 in the gas-phase. J. Am. Chem. Soc. 109, 1607–1614.Google Scholar
  34. 34.
    Straatsma T. P. and Berendsen H. J. C. (1988) Free-energy of iIonic hydration—analysis of a thermodynamic integration technique to evaluate free-energy differences by molecular-dynamics simulations. J. Chem. Phys. 89, 5876–5886.Google Scholar
  35. 35.
    Jarzynski C. (1997) Nonequilibrium equality for free energy differences. Phys. Rev. Lett. 78, 2690–2693.Google Scholar
  36. 35a.
    Sharma P., Steinbach P. J., Sharma M., Amin N. D., Barchi J. J., and Pant H. C. (1999) Identification of substrate binding site of cyclin-dependent kinase 5. J. Biol. Chem. 274, 9600–9606.PubMedGoogle Scholar
  37. 36.
    Dullweber F., Stubbs M. T., Musil D., Sturzebecher J., and Klebe G. (2001) Factorising ligand affinity: A combined thermodynamic and crystallographic study of trypsin and thrombin inhibition. J. Mol. Biol. 313, 593–614.PubMedGoogle Scholar
  38. 37.
    Ryde U. and Nilsson K. (2003) Quantum chemistry can locally improve protein crystal structures. J. Am. Chem. Soc. 125, 14,232–14,233.PubMedGoogle Scholar
  39. 38.
    Halgren T. A. (1996) Merck molecular force field.1. Basis, form, scope, parameterization, and performance of MMFF94. J. Comput. Chem. 17, 490–519.Google Scholar
  40. 39.
    Gilson M. K., Gilson H. S. R., and Potter M. J. (2003) Fast assignment of accurate partial atomic charges: An electronegativity equalization method that accounts for alternate resonance forms. J. Chem. Inf. Comput. Sci. 43, 1982–1997.PubMedGoogle Scholar
  41. 40.
    Vieth M., Hirst J. D., Kolinski A., and Brooks C. L. (1998) Assessing energy functions for flexible docking. J. Comput. Chem. 19, 1612–1622.Google Scholar
  42. 41.
    Wu G. S., Robertson D. H., Brooks C. L., and Vieth M. (2003) Detailed analysis of grid-based molecular docking: a case study of CDOCKER—a CHARMm-basedMD docking algorithm. J. Comput. Chem. 24, 1549–1562.PubMedGoogle Scholar
  43. 42.
    Li Z. Q. and Scheraga H. A. (1987) Monte-Carlo-minimization approach to the multiple-minima problem in protein folding. Proc. Natl. Acad. Sci. USA 84(19), 6611–6615.PubMedGoogle Scholar
  44. 43.
    Abagyan R. A. and Totrov M. (1999) Ab initio folding of peptides by the optimal-bias Monte Carlo minimization procedure. J. Comp. Phys. 151, 402–421.Google Scholar
  45. 43a.
    Steinbach P. J. (2004) Exploring peptide energy landscapes: a test of force fields and implicit solvent models. Proteins 57, 665–677.PubMedGoogle Scholar
  46. 44.
    Steinbach P. J. and Brooks B. R. (1993) Protein hydration elucidated by molecular-dynamics simulation. Proc. Natl. Acad. Sci. USA 90(19), 9135–9139.PubMedGoogle Scholar
  47. 45.
    Steinbach P. J. and Brooks B. R. (1996) Hydrated myoglobin’s anharmonic fluctuations are not primarily due to dihedral transitions. Proc. Natl. Acad. Sci. USA 93, 55–59.PubMedGoogle Scholar
  48. 46.
    Luecke H., Schobert B., Richter H.-T., Cartailler J.-P., and Lanyi J. K. (1999) Structural changes in bacteriorhodopsin during ion transport at 2 angstrom resolution. Science 286, 255–260.PubMedGoogle Scholar
  49. 47.
    Bryant R. G. (1996) The dynamics of water-protein interactions. Annu. Rev. Biophys. Biomol. Struct. 25, 29–53.PubMedGoogle Scholar
  50. 48.
    Ooi T. (1994) Thermodynamics of protein-folding. Effects of hydration and electrostatic interactions. Adv. Biophys. 30, 105–154.PubMedGoogle Scholar
  51. 49.
    Ben-Naim A. (1980) Hydrophobic Interactions. Plenum Press, New York, NY.Google Scholar
  52. 50.
    Teeter M. M. (1991) Water-protein interactions: theory and experiment. Annu. Rev. Biophys. Biophys. Chem. 20, 577–600.PubMedGoogle Scholar
  53. 51.
    Otting G., Liepinsh E., and Wütrich K. (1991) Protein hydration in aqueous solution. Science 254, 974–980.PubMedGoogle Scholar
  54. 52.
    Bailly C., Chessari G., Carrasco C., Joubert A., Mann J., Wilson W. D., and Neidle S. (2003) Sequence-specific minor groove binding by bis-benzimidazoles: water molecules in ligand recognition. Nucleic Acids Res. 31, 1514–1524.PubMedGoogle Scholar
  55. 53.
    Poornima C. S. and Dean P. M. (1995) Hydration in drug design.1. Multiple hydrogen-bonding features of water molecules in mediating protein-ligand interactions. J. Comp. Aid. Mol. Des. 9, 500–512.Google Scholar
  56. 54.
    Poornima C. S. and Dean P. M. (1995) Hydration in drug design.3. Conserved water molecules at the ligand-binding sites of homologous proteins. J. Comp. Aid. Mol. Des. 9(6), 521–531.Google Scholar
  57. 55.
    Lazaridis T. and Karplus M. (1999) Effective energy function for proteins in solution. Proteins 35, 133–152.PubMedGoogle Scholar
  58. 56.
    Hassan S. A., Guarnieri F., and Mehler E. L. (2000) A general treatment of solvent effects based on screened Coulomb potentials. J. Phys. Chem. B. 104, 6478–6489.Google Scholar
  59. 57.
    Hassan S. A. and Mehler E. L. (2002) A critical analysis of continuum electrostatics: the screened Coulomb potential-implicit solvent model and the study of the alanine dipeptide and discrimination of misfolded structures of proteins. Proteins 47,45–61.PubMedGoogle Scholar
  60. 58.
    Warshel A. and Aqvist J. (1991) Electrostatic energy and macromolecular function. Annu. Rev. Biophys. Biophys. Chem. 20, 267–298.PubMedGoogle Scholar
  61. 59.
    Mehler E. L. and Warshel A. (2000) Comment on “a fast and simple method to calculate pProtonation states in proteins.” Proteins 40, 1–3.PubMedGoogle Scholar
  62. 60.
    Kassner R. J. (1972) Theoretical model for effects of local nonpolar heme environments on redox potentials in cytochromes. J. Am. Chem. Soc. 95, 2674.Google Scholar
  63. 61.
    Eisenman G. and Horn R. (1983) Ionic selectivity revisited. The role of kinetic and equilibrium processes in ion permeation through channels. J. Membr. Biol. 76,197.PubMedGoogle Scholar
  64. 62.
    Warshel A. and Papazyan A. (1998) Electrostatic effects in macromolecules: fundamental concepts and practical modeling. Curr. Opin. Struct. Biol. 8, 211–217.PubMedGoogle Scholar
  65. 63.
    Arora N. and Bashford D. (2001) Solvation energy density occlusion approximation for evaluation of desolvation penalties in biomolecular interactions. Proteins 43, 12–27.PubMedGoogle Scholar
  66. 64.
    Camacho C. J., Weng Z. P., Vajda S., and DeLisi C. (1999) Free energy landscapes of encounter complexes in protein-protein association. Biophys. J. 76, 1166–1178.PubMedGoogle Scholar
  67. 65.
    Muegge I. (2000) A knowledge-based scoring function for protein-ligand interactions: probing the reference state. Perspect. Drug Discov. 20, 99–114.Google Scholar
  68. 66.
    Palma P. N., Krippahl L., Wampler J. E., and Moura J. J. G. (2000) BiGGER: a new (soft) docking algorithm for predicting protein interactions. Proteins 39, 372–384.PubMedGoogle Scholar
  69. 67.
    Varnai P. and Warshel A. (2000) Computer simulation studies of the catalytic mechanism of human aldose reductase. J. Am. Chem. Soc. 122, 3849–3860.Google Scholar
  70. 68.
    Luo N., Mehler E., and Osman R. (1999) Specificity and catalysis of uracil DNA glycosylase. A molecular dynamics study of reactant and product complexes with DNA. Biochemistry 38, 9209–9220.PubMedGoogle Scholar
  71. 69.
    Mehler E. L., Fuxreiter M., Simon I., and Garcia-Moreno E. B. (2002) The role of hydrophobic microenvironment in modulating pKa dhifts in proteins. Proteins 48, 283.PubMedGoogle Scholar
  72. 70.
    Mehler E. L. and Guarnieri F. (1999) A self-consistent, microenvironment modulated screened Coulomb potential approximation to calculate pH dependent electrostatic effects in proteins. Biophys. J. 77, 3–22.PubMedGoogle Scholar
  73. 71.
    Bowie J. U., Luthy R., and Eisenberg D. (1991) A method to identify protein sequences that fold into a known three-dimensional structure. Science 253, 164–170.PubMedGoogle Scholar
  74. 72.
    Kleiger G., Beamer L. J., Grothe R., Mallick P., and Eisenberg D. (2000) The 1.7Å crystal structure of BPI: a study of how two dissimilar amino acid sequences can adopt the same fold. J. Mol. Biol. 299, 1019–1034.PubMedGoogle Scholar
  75. 73.
    Hassan S. A., Mehler E. L., Zhang D., and Weinstein H. (2003) Molecular dynamics simulations of peptides and proteins with a continuum electrostatic model based on screened Coulomb potentials. Proteins 51, 109–125.PubMedGoogle Scholar
  76. 74.
    Honig B. and Nicholls A. (1995) Classical electrostatics in biology and chemistry. Science 268, 1144–1149.PubMedGoogle Scholar
  77. 75.
    Fogolari F., Zuccato P., Esposito G., and Viglino P. (1999) Biomolecular electrostatics with the linearized Poisson-Boltzmann equation. Biophys. J. 76, 1.PubMedGoogle Scholar
  78. 76.
    Smith P. E. (1999) Computer simulation of cosolvent effects on hydrophobic hydration. J. Phys. Chem. B. 103, 525.Google Scholar
  79. 77.
    Mancera R. L. (1999) Influence of salt on hydrophobic effects: a molecular dynamics study using the modified hydration-shell hydrogen-bond model. J. Phys. Chem. B. 103, 3774.Google Scholar
  80. 78.
    Kokkoli E. and Zukoski C. F. (1998) Interactions between hydrophobic self-assembled monolayers. Effect of salt and the chemical potential of water on adhesion. Langmuir. 14, 1189.Google Scholar
  81. 79.
    Christenson H. K., Claesson P. M., and Parker J. L. (1992) Hydrophobic attraction. A reexamination of electrolyte effects. J. Phys. Chem. 96, 6725.Google Scholar
  82. 80.
    Jackson J. D. (1975) Classical Electrodynamics. 2nd Ed. Wiley.Google Scholar
  83. 81.
    Gilson M. K., Davis M. E., Luty B. A., and McCammon J. A. (1993) Computation of electrostatic forces on solvated molecules using the Poisson-Boltzmann equation. J. Phys. Chem. 97, 3591–3600.Google Scholar
  84. 82.
    Sharp K. A. (1995) Polyelectrolyte electrostatics. Salt dependence, entropic, and enthalpic contributions to free energy in the nonlinear Poisson-Boltzmann model. Biopolymers 36, 227.Google Scholar
  85. 83.
    Davis M. E., Madura J. D., Luty B. A., and McCammon J. A. (1991) Electrostatics and diffusion of molecules in solution: simulations with the University of ouston Brownian Dynamics program. Comp. Phys. Comm. 62, 187–197.Google Scholar
  86. 84.
    Madura J. D., Briggs J. M., Wade R. C., Davis M. E., Luty B. A., Ilin A., Antosiewics J., Gilson M. K., Bagheri B., Scott L. R., and McCammon J. A. (1995) Electrostatics and diffusion of molecules in solution: simulations with the University of Houston Brownian dynamics program. Comp. Phys. Commun. 91, 57–95.Google Scholar
  87. 85.
    Garcia-Moreno B., Dwyer J. J., Gittis A. G., Lattman E. E., Spencer D. S., and Stites W. E. (1997) Experimental measurement of the effective dielectric in the hydrophobic core of a protein. Biophys. Chem. 64, 211–224.PubMedGoogle Scholar
  88. 86.
    Sham Y. Y., Muegge I., and Warshel A. (1998) The effect of protein relaxation on charge-charge interactions and dielectric constants of proteins. Biophys. J. 74, 1744–1753.PubMedGoogle Scholar
  89. 87.
    Scarsi M., Apostolakis J., and Caflisch A. (1997) Continuum electrostatic energies of macromolecules in aqueous solutions. J. Phys. Chem. B. 101, 8098–8106.Google Scholar
  90. 88.
    Antosiewicz J., McCammon J. A., and Gilson M. K. (1994) Prediction of pH-dependent properties of proteins. J. Mol. Biol. 238, 415–436.PubMedGoogle Scholar
  91. 89.
    Pollock E. L., Alder B. J., and Pratt L. R. (1980) Relation between the local field at large distances from a charge or dipole and the dielectric constant. Proc. Natl. Acad. Sci. USA 77, 49–51.PubMedGoogle Scholar
  92. 90.
    Sham Y. Y., Chu Z. T., and Warshel A. (1997) Consistent calculations of pKa’s of ionizable residues in proteins: semi-microscopic and microscopic approaches. J. Phys. Chem. B. 101, 4458–4472.Google Scholar
  93. 91.
    Takashima S. and Schwan H. P. (1965) Dielectric dispersion of crystalline powders of amino acids, peptides and proteins. J. Phys. Chem. 69, 4176–4182.PubMedGoogle Scholar
  94. 92.
    Gilson M. K. and Honig B. H. (1986) The dielectric-constant of a folded protein. Biopolymers 25(11), 2097–2119.PubMedGoogle Scholar
  95. 93.
    Oda Y., Yamazaki T., Nagayama K., Kanaya S., Kuroda Y., and Nakamura H. (1994) Individual ionization constants of all the carboxyl groups in ribonuclease HI from Escherichia coli determined by NMR. Biochemistry 33, 5275–5284.PubMedGoogle Scholar
  96. 94.
    Nakamura H., Sakamoto T., and Wada A. (1988) A theoretical-study of the dielectric-constant of protein. Protein Eng. 2, 177–183.PubMedGoogle Scholar
  97. 95.
    King G., Lee F. S., and Warshel A. (1991) Microscopic simulations of macro scopic dielectric constants of solvated proteins. J. Chem. Phys. 91, 3647–3661.Google Scholar
  98. 96.
    Smith P. E., Brunne R. M., Mark A. E., and Vangunsteren W. F. (1993) Dielectric-properties of trypsin-inhibitor and lysozyme calculated from molecular-dynamics simulations. J. Phys. Chem. 97, 2009–2014.Google Scholar
  99. 97.
    Wesson L. and Eisenberg D. (1992) Atomic solvation parameters applied to molecular dynamics of proteins in solution. Protein Sci. 1(2), 227–235.PubMedGoogle Scholar
  100. 98.
    Ooi T., Oobatake M., Némethy G., and Scheraga H. A. (1987) Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides. Proc. Natl. Acad. Sci. USA 84, 3086–3090.PubMedGoogle Scholar
  101. 99.
    Still W. C., Tempczyk A., Hawley R. C., and Hendrickson T. (1990) Semi-analytical treatment of solvation for molecular mechanics and dynamics. J. Am. Chem. Soc. 112, 6127–6129.Google Scholar
  102. 100.
    Hassan S. A., Guarnieri F., and Mehler E. L. (2000) Characterization of hydrogen bonding in a continuum solvent model. J. Phys. Chem. B. 104, 6490–6498.Google Scholar
  103. 101.
    Warshel A. and Russell S. T. (1984) Calculation of electrostatic interactions in biological systems and in solutions. Quart. Rev. Biophys. 17, 283–422.Google Scholar
  104. 102.
    Russell S. T. and A. W. (1985) Calculations of electrostatic energies in proteins. J. Mol. Biol. 185, 389–404.PubMedGoogle Scholar
  105. 103.
    Qiu D., Shenkin P. S., Hollinger F. P., and Still W. C. (1997) The GB/SA continuum model for solvation. A fast analytical method for the calculation of approximate Born radii. J. Phys. Chem. B. 101, 3005–3014.Google Scholar
  106. 104.
    Schaefer M. and Karplus M. (1996) A comprehensive analytical treatment of continuum electrostatics. J. Phys. Chem. 100, 1578–1599.Google Scholar
  107. 105.
    Ghosh A., Rapp C., and Friesner R. A. (1998) Generalized Born model based on a surface area formulation. J. Phys. Chem. B. 102, 10,983.Google Scholar
  108. 106.
    Dominy B. N. and Brooks I., C.L. (1999) Development of a generalized Born model parametrization for proteins and nucleic acids. J. Phys. Chem. B. 103, 3765–3773.Google Scholar
  109. 107.
    Onufriev A., Bashford D., and Case D. A. (2000) Modification of the generalized Born model suitable for macromolecules. J. Phys. Chem. B. 104, 3712–3720.Google Scholar
  110. 108.
    Zhu J. A., Shi Y. Y., and Liu H. Y. (2002) Parametrization of a generalized Born/solvent-accessible surface area model and applications to the simulation of protein dynamics. J. Phys. Chem. B. 106,4844.Google Scholar
  111. 109.
    Lee M. S., Salsbury F. R., and Brooks C. L. (2002) Novel generalized Born methods. J. Chem. Phys. 116, 10,606–10,614.Google Scholar
  112. 110.
    Lorentz H. A. (1952) Theory of Electrons. Dover, New York, NY.Google Scholar
  113. 111.
    Debye P. (1929) Polar Molecules. Dover, New York, NY.Google Scholar
  114. 112.
    Debye P. and Pauling L. (1925) The inter-ionic attraction theory of ionized solutes. IV. The influence of variation of dielectric constant on the limiting law for small concentrations. J. Am. Chem. Soc. 47, 2129–2134.Google Scholar
  115. 113.
    Sack V. H. (1926) The dielectric constant of electrolytes. Phys. Z. 27, 206–208.Google Scholar
  116. 114.
    Sack V. H. (1927) The dielectric constants of solutions of electrolytes at small concentrations. Phys. Z. 28, 199–210.Google Scholar
  117. 115.
    Bucher M. and Porter T. L. (1986) Analysis of the Born model for hydration of ions. J. Phys. Chem. 90, 3406–3411.Google Scholar
  118. 116.
    Ehrenson S. (1989) Continuum radial dielectric functions for ion and dipole solution systems. J. Comp. Chem. 10, 77–93.Google Scholar
  119. 117.
    Mehler E. L. (1996) The Lorentz-Debye-Sack theory and dielectric screening of electrostatic effects in proteins and nucleic acids, in Molecular Electrostatic Potential: Concepts and Applications. (Murray J. S. and Sen K., eds.) Elsevier Science, Amsterdam, The Netherlands, pp. 371–405.Google Scholar
  120. 118.
    Davis M. E. and McCammon J. A. (1990) Calculating electrostatic forces from grid-calculated potentials. J. Comp. Chem. 11,401.Google Scholar
  121. 119.
    Sharp K. (1991) Incorporating solvent and ionic screening into molecular dynamics using the finite-difference Poisson-Boltzman method. J. Comp. Chem. 12, 454–468.Google Scholar
  122. 120.
    Myers J. K. and Pace C. N. (1996) Hydrogen bonding stabilizes globular proteins. Biophys. J. 71, 2033–2039.PubMedGoogle Scholar
  123. 121.
    Pace C. N. (2001) Polar group burial contributes more to protein stability than nonpolar group burial. Biochemistry 40, 310–313.PubMedGoogle Scholar
  124. 122.
    Hassan S. A. and Mehler E. L. (2001) A general screened Coulomb potential based implicit solvent model: calculation of secondary structure of small peptides. Int. J. Quant. Chem. 83, 193–202.Google Scholar
  125. 123.
    Hassan S. A., Mehler E. L., and Weinstein H. (2002) Structure calculations of protein segments connecting domains with defined secondary structure: A simulated annealing Monte Carlo combimed with biased scaled collective variables technique, in Lecture Notes in Computational Science and Engineering. (Hark K. and Schlick T., eds.) Springer Verlag, New York, NY, pp. 197–231.Google Scholar
  126. 123a.
    Hassan S. A. (2004) Intermolecular potentials of mean force of amino acids side chain interactions in aqueous medium. J. Phys. Chem. B 50, 19,501–19,509.Google Scholar
  127. 124.
    Privalov P. L. and Makhatadze G. I. (1993) Contribution of hydration to protein folding thermodynamics. II.The entropy and Gibbs energy of hydration. J. Mol. Biol. 232, 660.PubMedGoogle Scholar
  128. 125.
    Makhatadze G. I. and Privalov P. L. (1993) Contribution of hydration to protein folding thermodynamics. I. The enthalpy of hydration. J. Mol. Biol. 232, 639.PubMedGoogle Scholar
  129. 126.
    Davis A. M. and Teague S. J. (1999) Hydrogen bonding, hydrophobic interactions, and failure of the rigid receptor hypothesis. Angew. Chem, Int. Ed. 38, 736–749.Google Scholar
  130. 127.
    Tanford C. (1973) The Hydrophobic Effect. Formation of Micelles and Biological Membranes. Wiley-Interscience, New York, NY.Google Scholar
  131. 128.
    Fink A. L. (1998) Protein aggregation: folding aggregates, inclusion bodies and amyloid. Folding Des. 3, R9.Google Scholar
  132. 129.
    Cheng Y.-K. and Rossky P. J. (1998) Surface topography dependence of biomolecular hydrophobic hydration. Nature 392, 696.PubMedGoogle Scholar
  133. 130.
    Choe S. E., Li L., Matsudaira P. T., and Wagner G. (2000) Differential stabilization of two hydrophobic cores in the transition state of the villin 14T folding reaction. J. Mol. Biol. 304, 99.PubMedGoogle Scholar
  134. 131.
    Hadi M. Z., Ginalski K., Nguyen L. H., and Wilson III D. M. (2002) Determinant in nuclease specificity of ape 1 and ape2, human homogues of scherichia coli exonuclease III. J. Mol. Biol. 316, 853.PubMedGoogle Scholar
  135. 132.
    Starich M. R., et al. (1998) The solution structure of the Leu22→Val mutant AREA DNA binding domain complexed with a TGATAG core element defines a role for hydrophobic packing in the determination of specificity. J. Mol. Biol. 277, 621.PubMedGoogle Scholar
  136. 133.
    Shiba T. Takatsu H., Nogi T., et al. (2002) Structural basis for recognition of acidic-cluster dileucine sequence by GGA1. Nature 415, 937–941.PubMedGoogle Scholar
  137. 134.
    Peng X. and Jonas J. (1994) High-pressure NMR study of the dissociation of arc repressor. Biochemistry 33, 8323.PubMedGoogle Scholar
  138. 135.
    Nelson C. J., LaConte M. J., and Bowler B. E. (2001) Direct detection of heat and cold denaturation for partial unfolding of a protein. J. Am. Chem. Soc. 123, 7453.PubMedGoogle Scholar
  139. 136.
    Zhang J., Peng X., Jonas A., and Jonas J. (1995) NMR study of the cold, heat, and pressure unfolding of ribonuclease A. Biochemistry 34, 8631.PubMedGoogle Scholar
  140. 137.
    Hummer G., Garde S., Garcia A. E., Paulaitis M. E., and Pratt L. R. (1998) The pressure dependence of hydrophobic interactions is consistent with the observed pressure denaturation of proteins. Proc. Nat. Acad. Sci. (USA) 95, 1552.Google Scholar
  141. 138.
    Wagner F. and Simonson T. (1999) Implicit solvent models: combining an analytical formulation of continuum electrostatics with simple models of the hydrophobic effect. J. Comp. Chem. 20, 322–335.Google Scholar
  142. 139.
    Cramer C. J. and Truhlar D. G. (1992) An SCF solvation model for the hydro-phobic effect and absolute free energies of aqueous solvation. Science. 256, 213–217.Google Scholar
  143. 140.
    Simonson T. and Brunger A. T. (1994) Solvation free energies estimated from macroscopic continuum theory: an accuracy assessment. J. Phys. Chem. 98, 4683–4694.Google Scholar
  144. 141.
    Lum K., Chandler D., and Weeks J. D. (1999) Hydrophobicity at small and large length scales. J. Phys. Chem. B. 103, 4570.Google Scholar
  145. 142.
    Reiss H. (1965) A acaled particle methods in the statistical thermodynamics of fluids. Adv. Chem. Phys. 9, 1.Google Scholar
  146. 143.
    Tolman R. C. (1949) The effect of droplet size on surface tension. J. Chem. Phys. 17, 333.Google Scholar
  147. 144.
    Pratt E. A. and Chandler D. (1980) Effect of solute-solvent attractive forces on hydrophobic correlations. J. Chem. Phys. 73, 3434.Google Scholar
  148. 145.
    Pratt L. R. and Chandler D. (1977) Theory of hydrophobic effect. J. Chem. Phys. 67, 3683.Google Scholar
  149. 146.
    Reiss H., Frisch H. L., and Lebowitz J. L. (1959) Statistical mechanics of rigid spheres. J. Chem. Phys. 31, 369.Google Scholar
  150. 147.
    Pierotti R. A. (1963) Solubility of gases in liquids. J. Phys. Chem. 67, 1840.Google Scholar
  151. 148.
    Stillinger F. H. (1973) J. Solution Chem. 2, 141.Google Scholar
  152. 149.
    Chandler D. (1987) Introduction to Modern Statistical Mechanics. Oxford University Press, New York, NY.Google Scholar
  153. 150.
    Huang D. M. and Chandler D. (2002) The hydrophobic effect and the influence of solute-solvent attractions. J. Phys. Chem. B. 106, 2047.Google Scholar
  154. 151.
    Weeks J. D., Katsov K., and Vollmayr K. (1998) Roles of repulsive and attractive forces in determining the structure of nonuniform liquids: generalized mean field theory. Phys. Rev. Lett. 81, 4400.Google Scholar
  155. 151a.
    Jorgensen W. L. (1982) Quantum and statistical mechanical studies of liquids. Monte Carlo simulation of n-butane in water. Conformational evidence for hydrophobic effect. J. Chem. Phys. 77, 5757–5765.Google Scholar
  156. 152.
    Pashley R. M., McGuiggan P. M., Ninham B. W., and Al. E. (1985) Attractive forces between uncharged hydrophobic surfaces. Direct measurements in aqueous solution. Science 229, 1088.PubMedGoogle Scholar
  157. 153.
    Christenson H. K. and Claesson P. M. (1988) Cavitation and the interaction between macroscopic hydrophobic surfaces. Science 239, 390.PubMedGoogle Scholar
  158. 154.
    Christenson H. K. (1992) Modern Approaches to Wettability: Theory and Applications (Schrader M.E. and Loeb G. eds. Plenum, New York, NY.Google Scholar
  159. 155.
    Wallqvist A. and Berne B. J. (1995) Computer simulation of hydrophobic hydration forces on stacked plates at short range. J. Phys. Chem. 99, 2893.Google Scholar
  160. 156.
    Karplus M. and McCammon J. A. (2002) Molecular dynamics simulations of biomolecules. Nature Struct. Biol. 9, 646–652.PubMedGoogle Scholar
  161. 157.
    Andricioaei I. and Karplus M. (2001) On the calculation of entropy from covariance matrices of the atomic fluctuations. J. Chem. Phys. 115, 6289–6292.Google Scholar
  162. 158.
    Levy R. M., Karplus M., Kushick J., and Perahia D. (1984) Evaluation of the configurational entropy for proteins—application to molecular-dynamics simulations of an alpha-helix. Macromolecules 17, 1370–1374.Google Scholar
  163. 159.
    Brady J. and Karplus M. (1985) Configurational entropy of the alanine dipeptide in vacuum and in solution: a molecular dynamics study. J. A. Chem. Soc. 107, 6103–6105.Google Scholar
  164. 160.
    Eriksson M. A. and Nilsson L. (1995) Structure, thermodynamics and cooperativity of the glucocorticoid receptor DNA-binding domain in complex with different response elements. Molecular dynamics simulation and free energy perturbation studies. J. Mol. Biol. 253, 453-72.Google Scholar
  165. 161.
    van der Vegt N. F. A. and van Gunsteren W. F. (2004) Entropic contributions in cosolvent binding to hydrophobic solutes in water. J. Phys. Chem. B 108,1056–1064.Google Scholar
  166. 162.
    Swanson J. M. J., Henchman R. H., and McCammon J. A. (2004) Revisiting free energy calculations: a theoretical connection to MM/PBS A and direct calculation of the association free energy. Biophys. J. 86, 67–74.PubMedGoogle Scholar
  167. 163.
    Amzel L. M. (1997) Loss of translational entropy in binding, folding, and catalysis. Proteins. 28, 144–149.PubMedGoogle Scholar
  168. 164.
    Daquino J. A., Gomez J., Hilser V. J., Lee K. H., Amzel L. M., and Freire E. (1996) The magnitude of the backbone conformational entropy change in protein folding. Proteins 25, 143–156.Google Scholar
  169. 165.
    Lee K. H., Xie D., Freire E., and Amzel L. M. (1994) Estimation of changes in side-chain configurational entropy in binding and folding—general-methods and application to helix formation. Proteins 20, 68–84.PubMedGoogle Scholar
  170. 166.
    Zwanzig R. W. (1954) High-temperature equation of state by a perturbation method. I. Nonpolar gases. J. Chem. Phys. 22, 1420.Google Scholar
  171. 167.
    Kollman P. A. (1993) Free energy calculations: Applications to chemical and biochemical phenomena. Chem. Rev. 93, 2395–2417.Google Scholar
  172. 168.
    Torrie G. M. and Valleau J. P. (1977) Nonphysical sampling distributions in Monte Carlo free energy estimation:Umbrella sampling. J. Comput. Phys. 23, 187–189.Google Scholar
  173. 169.
    Bennett C. H. (1976) Efficient estimation of free energy differences from Monte Carlo data. J. Comput. Phys. 22, 245–268.Google Scholar
  174. 170.
    Bash P. A., Singh U. C., Brown F. K., Langridge R., and Kollman P. (1987) Calculation of the relative change in binding free energy of a protein-inhibitor complex. Science 235, 574–576.PubMedGoogle Scholar
  175. 171.
    Wong C. F. and McCammon J. A. (1986) Dynamics and design of enzymes and inhibitors. J. Am. Chem. Soc. 108, 3830–3832.Google Scholar
  176. 172.
    Weiner S., Kollman P., Case D., Singh U. C., Ghio C., Alagona G., Profeta S. J., and Weiner P. (1984) A new force field for molecular mechanical simulation of nucleic acids and proteins. J. Am. Chem. Soc. 106, 765–784.Google Scholar
  177. 173.
    van Gunsteren W. F. (1987) GROMOS. Groningen Molecular Simulation Computer Program Package, University of Groningen. The Netherlands.Google Scholar
  178. 174.
    Kirkwood J. G. (1935) Statistical mechanics of fluid mixtures. J. Chem. Phys. 3, 300–313.Google Scholar
  179. 175.
    Olson M. A. and Reinke L. T. (2000) Modeling implicit reorganization in continuum descriptions of protein-protein interactions. Proteins 38, 115–119.PubMedGoogle Scholar
  180. 176.
    Frauenfelder H. (1995) Complexity in proteins. Nature Struct. Biol. 2, 821–823.PubMedGoogle Scholar
  181. 177.
    Frauenfelder H., Sligar S. G., and Wolynes P. G. (1991) The energy landscapes and motions of proteins. Science. 254, 1598–1603.Google Scholar
  182. 178.
    Noguti T. and Go N. (1989) Structural basis of hierarchical multiple substates of a protein. Proteins 5, 97–103.PubMedGoogle Scholar
  183. 179.
    Elber R. and Karplus M. (1987) Multiple conformational states of proteins: A molecular dynamics analysis of myoglobin. Science 235, 318–321.PubMedGoogle Scholar
  184. 180.
    Leeson D. T. and Wiersma D. A. (1995) Looking into the energy landscape of myoglobin. Nature Struct. Biol. 2, 848–851.PubMedGoogle Scholar
  185. 181.
    Carlson H. A. and McCammon A. (2000) Accomodating protein flexibility in computational drug design. Mol. Pharmacol. 57, 213–218.PubMedGoogle Scholar
  186. 182.
    Gane P. J. and Dean P. M. (2000) Recent advances in structure-based drug design. Curr. Opin. Struct. Biol. 10, 401–404.PubMedGoogle Scholar
  187. 183.
    Bouzida D., Rejto P. A., Arthurs S., Colson A. B., Freer S. T., Gehlhaar D. K., Larson V., Luty B. A., Rose P. W., and Verkhivker G. M. (1999) Computer simulations of ligand-protein binding with ensembles of protein conformations: A Monte Carlo study of HIV-1 protease binding energy landscapes. Int. J. Quantum Chem. 72, 73–84.Google Scholar
  188. 184.
    Carlson H. A., Masukawa K. M., and McCammon A. (1999) Method for including the dynamic fluctuations of a protein in a computer-aided drug design. J. Phys. Chem. A. 103, 10,213–10,219.Google Scholar
  189. 185.
    Gallicchio E., Kubo M. M., and Levy R. M. (1998) Entropy-enthalpy compensation in solvation and ligand binding revisited. J. Am. Chem. Soc. 120, 4526–4527.Google Scholar
  190. 186.
    Lee C. and Irizarry K. (2001) The GeneMine System for genome/proteome annotation and collaborative data mining. IBM Systems Journal. 50, 592–603.Google Scholar
  191. 187.
    Kraulis P. J. (1991) MOLSCRIPT: A program to produce both detailed and schematic plots of protein structures. J. Appl. Cryst. 24, 946–950.Google Scholar
  192. 188.
    Merritt E. A. and Bacon D. J. (1997) Raster3D: photorealistic molecular graphics, in Methods in Enzymology, Vol. 277, Macromolecular Crystallography, Pt. B., (Carter C. W., Jr. and Sweet R. M., eds.) Academic Press, San Diego, CA, pp. 505–524.Google Scholar
  193. 189.
    Brooks B. R., Bruccoleri R. E., Olafson B. D., States D. J., Swaminathan S., and Karplus M. (1983) CHARMM: A program for macromolecular energy, minimization and dynamics calculations. J. Comput. Chem. 4, 187–217.Google Scholar
  194. 190.
    Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., et al. (2001) Gaussian 98. Gaussian, Pittsburgh, PA.Google Scholar
  195. 191.
    Goodsell D. S. and Olson A. J. (1990) Automated docking of substrates to proteins by simulated annealing. Proteins 8, 195.PubMedGoogle Scholar
  196. 192.
    Goodsell D. S., Morris G. M., and Olson A. J. (1996) Automated docking of flexible ligands: applications of AutoDock. J. Mol. Recognit. 9, 1.PubMedGoogle Scholar
  197. 193.
    Morris G. M., Goodsell D. S., Huey R., and Olson A. J. (1996) Distributed automated docking of flexible ligands to proteins: parallel applications of Auto-Dock 2.4. J. Comp. Aid. Mol. Des. 10, 293.Google Scholar
  198. 194.
    Petrey D., Xiang Z. X., Tang C. L., Xie L., Gimpelev M., Mitros T., Soto C. S., Goldsmith-Fischman S., Kernytsky A., Schlessinger A., Koh I. Y. Y., Alexov E., and Honig B. (2003) Using multiple structure alignments, fast model building, and energetic analysis in fold recognition and homology modeling.Proteins 53, 430–435.PubMedGoogle Scholar
  199. 195.
    Pikis A., Donkersloot J. A., Rodriguez W. J., and Keith J. M. (1998) A conservative amino acid mutation in the chromosome-encoded dihydrofolate reductase confers trimethoprim resistance in Streptococcus pneumoniae. J. Infect. Dis. 178(3), 700–706.Google Scholar
  200. 195a.
    Levitt M. (1992) Accurate modeling of protein conformation by automatic segment matching. J. Mol. Biol. 226, 507–533.PubMedGoogle Scholar
  201. 196.
    Matthews D. A., Bolin J. T., Burridge J. M., Filman D. J., Volz K. W., Kaufman B. T., Beddell C. R., Champness J. N., Stammers D. K., and Kraut J. (1985) Refined crystal-structures of Escherichia-coli and chicken liver dihydrofolate-reductase containing bound trimethoprim. J. Biol. Chem. 260, 381–391.PubMedGoogle Scholar
  202. 197.
    Abagyan R. and Totrov M. (1994) Biased probability Monte-Carlo conformational searches and electrostatic calculations for peptides and proteins. J. Mol. Biol. 235, 983–1002.PubMedGoogle Scholar
  203. 198.
    Talhout R. and Engberts J. B. (2001) Thermodynamic analysis of binding of p-substituted benzamidines to trypsin. Eur. J. Biochem. 268, 1554–1560.PubMedGoogle Scholar
  204. 199.
    Bachovchin W. W. (2001) Contributions of NMR spectroscopy to the study of hydrogen bonds in serine protease active sites. Magnet. Res. Chem. 39, S199–S213.Google Scholar
  205. 200.
    Sanschagrin P. C. and Kuhn L. A. (1998) Cluster analysis of consensus water sites in thrombin and trypsin shows conservation between serine proteases and contributions to ligand specificity. Protein Sci. 7, 2054–2064.PubMedGoogle Scholar
  206. 201.
    Steinbach P. J. (1998) Introduction to Macromolecular Simulation, in Biophysics Textbook On-line, (Bloomfield V., ed.), Biophysical Society: Bethesda, MD. Website: http://www.biophysics.org/btol/.Google Scholar
  207. 202.
    Steinbach P. J. and Brooks B. R. (1994) New spherical-cutoff methods for long-range forces in macromolecular simulation. J. Comput. Chem. 15(7), 667–683.Google Scholar
  208. 203.
    Darden T., York D., and Pedersen L. (1993) Particle mesh Eewald—an N.Log(N) method for ewald sums in large systems. J. Chem. Phys. 98(12), 10,089–10,092.Google Scholar
  209. 204.
    Sagui C. and Darden T. A. (1999) Molecular dynamics simulations of biomolecules: Long-range electrostatic effects. Ann. Rev. Biophys. Biomol. Struct. 28, 155–179.Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • Sergio A. Hassan
    • 1
  • Luis Gracia
    • 2
  • Geetha Vasudevan
    • 3
  • Peter J. Steinbach
    • 1
  1. 1.Center for Molecular Modeling, Division of Computational Bioscience, Center for Information TechnologyNational Institutes of HealthBethesda
  2. 2.Department of Physiology and Biophysics, Weill Medical CollegeCornell UniversityNew York
  3. 3.Scientific Computing, Medarex Inc.Sunnyvale

Personalised recommendations