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. 1995 Sep;4(9):1881–1903. doi: 10.1002/pro.5560040923

A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-1-protease inhibitor design.

A Wallqvist 1, R L Jernigan 1, D G Covell 1
PMCID: PMC2143230  PMID: 8528086

Abstract

The interface between protein receptor-ligand complexes has been studied with respect to their binary interatomic interactions. Crystal structure data have been used to catalogue surfaces buried by atoms from each member of a bound complex and determine a statistical preference for pairs of amino-acid atoms. A simple free energy model of the receptor-ligand system is constructed from these atom-atom preferences and used to assess the energetic importance of interfacial interactions. The free energy approximation of binding strength in this model has a reliability of about +/- 1.5 kcal/mol, despite limited knowledge of the unbound states. The main utility of such a scheme lies in the identification of important stabilizing atomic interactions across the receptor-ligand interface. Thus, apart from an overall hydrophobic attraction (Young L, Jernigan RL, Covell DG, 1994, Protein Sci 3:717-729), a rich variety of specific interactions is observed. An analysis of 10 HIV-1 protease inhibitor complexes is presented that reveals a common binding motif comprised of energetically important contacts with a rather limited set of atoms. Design improvements to existing HIV-1 protease inhibitors are explored based on a detailed analysis of this binding motif.

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Selected References

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  1. Ascenzi P., Amiconi G., Menegatti E., Guarneri M., Bolognesi M., Schnebli H. P. Binding of the recombinant proteinase inhibitor eglin c from leech Hirudo medicinalis to human leukocyte elastase, bovine alpha-chymotrypsin and subtilisin Carlsberg: thermodynamic study. J Enzyme Inhib. 1988;2(3):167–172. doi: 10.3109/14756368809040723. [DOI] [PubMed] [Google Scholar]
  2. Ben-Naim A. Solvent effects on protein association and protein folding. Biopolymers. 1990 Feb 15;29(3):567–596. doi: 10.1002/bip.360290312. [DOI] [PubMed] [Google Scholar]
  3. Ben-Naim A., Ting K. L., Jernigan R. L. Solvation thermodynamics of biopolymers. I. Separation of the volume and surface interactions with estimates for proteins. Biopolymers. 1989 Jul;28(7):1309–1325. doi: 10.1002/bip.360280711. [DOI] [PubMed] [Google Scholar]
  4. Ben-Naim A., Ting K. L., Jernigan R. L. Solvation thermodynamics of biopolymers. II. Correlations between functional groups. Biopolymers. 1989 Jul;28(7):1327–1337. doi: 10.1002/bip.360280712. [DOI] [PubMed] [Google Scholar]
  5. Ben-Naim A., Ting K. L., Jernigan R. L. Solvent effect on binding thermodynamics of biopolymers. Biopolymers. 1990 May-Jun;29(6-7):901–919. doi: 10.1002/bip.360290604. [DOI] [PubMed] [Google Scholar]
  6. Benner S. A., Jenny T. F., Cohen M. A., Gonnet G. H. Predicting the conformation of proteins from sequences. Progress and future progress. Adv Enzyme Regul. 1994;34:269–353. doi: 10.1016/0065-2571(94)90021-3. [DOI] [PubMed] [Google Scholar]
  7. Bennett M. J., Choe S., Eisenberg D. Domain swapping: entangling alliances between proteins. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3127–3131. doi: 10.1073/pnas.91.8.3127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bernstein F. C., Koetzle T. F., Williams G. J., Meyer E. F., Jr, Brice M. D., Rodgers J. R., Kennard O., Shimanouchi T., Tasumi M. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol. 1977 May 25;112(3):535–542. doi: 10.1016/s0022-2836(77)80200-3. [DOI] [PubMed] [Google Scholar]
  9. Biou V., Gibrat J. F., Levin J. M., Robson B., Garnier J. Secondary structure prediction: combination of three different methods. Protein Eng. 1988 Sep;2(3):185–191. doi: 10.1093/protein/2.3.185. [DOI] [PubMed] [Google Scholar]
  10. Bode W. The transition of bovine trypsinogen to a trypsin-like state upon strong ligand binding. II. The binding of the pancreatic trypsin inhibitor and of isoleucine-valine and of sequentially related peptides to trypsinogen and to p-guanidinobenzoate-trypsinogen. J Mol Biol. 1979 Feb 5;127(4):357–374. doi: 10.1016/0022-2836(79)90227-4. [DOI] [PubMed] [Google Scholar]
  11. Bohacek R. S., McMartin C. Definition and display of steric, hydrophobic, and hydrogen-bonding properties of ligand binding sites in proteins using Lee and Richards accessible surface: validation of a high-resolution graphical tool for drug design. J Med Chem. 1992 May 15;35(10):1671–1684. doi: 10.1021/jm00088a002. [DOI] [PubMed] [Google Scholar]
  12. Burley S. K., Petsko G. A. Aromatic-aromatic interaction: a mechanism of protein structure stabilization. Science. 1985 Jul 5;229(4708):23–28. doi: 10.1126/science.3892686. [DOI] [PubMed] [Google Scholar]
  13. Caflisch A., Miranker A., Karplus M. Multiple copy simultaneous search and construction of ligands in binding sites: application to inhibitors of HIV-1 aspartic proteinase. J Med Chem. 1993 Jul 23;36(15):2142–2167. doi: 10.1021/jm00067a013. [DOI] [PubMed] [Google Scholar]
  14. Casari G., Sippl M. J. Structure-derived hydrophobic potential. Hydrophobic potential derived from X-ray structures of globular proteins is able to identify native folds. J Mol Biol. 1992 Apr 5;224(3):725–732. doi: 10.1016/0022-2836(92)90556-y. [DOI] [PubMed] [Google Scholar]
  15. Chen X., Tropsha A. Relative binding free energies of peptide inhibitors of HIV-1 protease: the influence of the active site protonation state. J Med Chem. 1995 Jan 6;38(1):42–48. doi: 10.1021/jm00001a009. [DOI] [PubMed] [Google Scholar]
  16. Chen Z., Bode W. Refined 2.5 A X-ray crystal structure of the complex formed by porcine kallikrein A and the bovine pancreatic trypsin inhibitor. Crystallization, Patterson search, structure determination, refinement, structure and comparison with its components and with the bovine trypsin-pancreatic trypsin inhibitor complex. J Mol Biol. 1983 Feb 25;164(2):283–311. doi: 10.1016/0022-2836(83)90078-5. [DOI] [PubMed] [Google Scholar]
  17. Chothia C., Lesk A. M. The relation between the divergence of sequence and structure in proteins. EMBO J. 1986 Apr;5(4):823–826. doi: 10.1002/j.1460-2075.1986.tb04288.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Chou P. Y., Fasman G. D. Empirical predictions of protein conformation. Annu Rev Biochem. 1978;47:251–276. doi: 10.1146/annurev.bi.47.070178.001343. [DOI] [PubMed] [Google Scholar]
  19. Connelly P. R., Aldape R. A., Bruzzese F. J., Chambers S. P., Fitzgibbon M. J., Fleming M. A., Itoh S., Livingston D. J., Navia M. A., Thomson J. A. Enthalpy of hydrogen bond formation in a protein-ligand binding reaction. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1964–1968. doi: 10.1073/pnas.91.5.1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Connolly M. L. Solvent-accessible surfaces of proteins and nucleic acids. Science. 1983 Aug 19;221(4612):709–713. doi: 10.1126/science.6879170. [DOI] [PubMed] [Google Scholar]
  21. Covell D. G. Lattice model simulations of polypeptide chain folding. J Mol Biol. 1994 Jan 21;235(3):1032–1043. doi: 10.1006/jmbi.1994.1055. [DOI] [PubMed] [Google Scholar]
  22. Dill K. A. Dominant forces in protein folding. Biochemistry. 1990 Aug 7;29(31):7133–7155. doi: 10.1021/bi00483a001. [DOI] [PubMed] [Google Scholar]
  23. Dorsey B. D., Levin R. B., McDaniel S. L., Vacca J. P., Guare J. P., Darke P. L., Zugay J. A., Emini E. A., Schleif W. A., Quintero J. C. L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem. 1994 Oct 14;37(21):3443–3451. doi: 10.1021/jm00047a001. [DOI] [PubMed] [Google Scholar]
  24. Dreyer G. B., Lambert D. M., Meek T. D., Carr T. J., Tomaszek T. A., Jr, Fernandez A. V., Bartus H., Cacciavillani E., Hassell A. M., Minnich M. Hydroxyethylene isostere inhibitors of human immunodeficiency virus-1 protease: structure-activity analysis using enzyme kinetics, X-ray crystallography, and infected T-cell assays. Biochemistry. 1992 Jul 28;31(29):6646–6659. doi: 10.1021/bi00144a004. [DOI] [PubMed] [Google Scholar]
  25. Eisenberg D., McLachlan A. D. Solvation energy in protein folding and binding. Nature. 1986 Jan 16;319(6050):199–203. doi: 10.1038/319199a0. [DOI] [PubMed] [Google Scholar]
  26. Empie M. W., Laskowski M., Jr Thermodynamics and kinetics of single residue replacements in avian ovomucoid third domains: effect on inhibitor interactions with serine proteinases. Biochemistry. 1982 May 11;21(10):2274–2284. doi: 10.1021/bi00539a002. [DOI] [PubMed] [Google Scholar]
  27. Erickson H. P. Co-operativity in protein-protein association. The structure and stability of the actin filament. J Mol Biol. 1989 Apr 5;206(3):465–474. doi: 10.1016/0022-2836(89)90494-4. [DOI] [PubMed] [Google Scholar]
  28. Finkelstein A. V., Janin J. The price of lost freedom: entropy of bimolecular complex formation. Protein Eng. 1989 Oct;3(1):1–3. doi: 10.1093/protein/3.1.1. [DOI] [PubMed] [Google Scholar]
  29. Fischer D., Lin S. L., Wolfson H. L., Nussinov R. A geometry-based suite of molecular docking processes. J Mol Biol. 1995 Apr 28;248(2):459–477. doi: 10.1016/s0022-2836(95)80063-8. [DOI] [PubMed] [Google Scholar]
  30. Fitzgerald P. M., McKeever B. M., VanMiddlesworth J. F., Springer J. P., Heimbach J. C., Leu C. T., Herber W. K., Dixon R. A., Darke P. L. Crystallographic analysis of a complex between human immunodeficiency virus type 1 protease and acetyl-pepstatin at 2.0-A resolution. J Biol Chem. 1990 Aug 25;265(24):14209–14219. [PubMed] [Google Scholar]
  31. Gao J., Chou L. W., Auerbach A. The nature of cation-pi binding: interactions between tetramethylammonium ion and benzene in aqueous solution. Biophys J. 1993 Jul;65(1):43–47. doi: 10.1016/S0006-3495(93)81031-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Garnier J., Osguthorpe D. J., Robson B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol. 1978 Mar 25;120(1):97–120. doi: 10.1016/0022-2836(78)90297-8. [DOI] [PubMed] [Google Scholar]
  33. Gerloff D. L., Benner S. A. A consensus prediction of the secondary structure for the 6-phospho-beta-D-galactosidase superfamily. Proteins. 1995 Apr;21(4):273–281. doi: 10.1002/prot.340210402. [DOI] [PubMed] [Google Scholar]
  34. Ghosh A. K., Thompson W. J., Fitzgerald P. M., Culberson J. C., Axel M. G., McKee S. P., Huff J. R., Anderson P. S. Structure-based design of HIV-1 protease inhibitors: replacement of two amides and a 10 pi-aromatic system by a fused bis-tetrahydrofuran. J Med Chem. 1994 Aug 5;37(16):2506–2508. doi: 10.1021/jm00042a002. [DOI] [PubMed] [Google Scholar]
  35. Gibrat J. F., Garnier J., Robson B. Further developments of protein secondary structure prediction using information theory. New parameters and consideration of residue pairs. J Mol Biol. 1987 Dec 5;198(3):425–443. doi: 10.1016/0022-2836(87)90292-0. [DOI] [PubMed] [Google Scholar]
  36. Greer J. Comparative model-building of the mammalian serine proteases. J Mol Biol. 1981 Dec 25;153(4):1027–1042. doi: 10.1016/0022-2836(81)90465-4. [DOI] [PubMed] [Google Scholar]
  37. Greer J. Comparative modeling methods: application to the family of the mammalian serine proteases. Proteins. 1990;7(4):317–334. doi: 10.1002/prot.340070404. [DOI] [PubMed] [Google Scholar]
  38. Greer J., Erickson J. W., Baldwin J. J., Varney M. D. Application of the three-dimensional structures of protein target molecules in structure-based drug design. J Med Chem. 1994 Apr 15;37(8):1035–1054. doi: 10.1021/jm00034a001. [DOI] [PubMed] [Google Scholar]
  39. Grinde B., Cameron C. E., Leis J., Weber I. T., Wlodawer A., Burstein H., Bizub D., Skalka A. M. Mutations that alter the activity of the Rous sarcoma virus protease. J Biol Chem. 1992 May 15;267(14):9481–9490. [PubMed] [Google Scholar]
  40. Grinde B., Cameron C. E., Leis J., Weber I. T., Wlodawer A., Burstein H., Skalka A. M. Analysis of substrate interactions of the Rous sarcoma virus wild type and mutant proteases and human immunodeficiency virus-1 protease using a set of systematically altered peptide substrates. J Biol Chem. 1992 May 15;267(14):9491–9498. [PubMed] [Google Scholar]
  41. Ho D. D., Toyoshima T., Mo H., Kempf D. J., Norbeck D., Chen C. M., Wideburg N. E., Burt S. K., Erickson J. W., Singh M. K. Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. J Virol. 1994 Mar;68(3):2016–2020. doi: 10.1128/jvi.68.3.2016-2020.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Holloway M. K., Wai J. M., Halgren T. A., Fitzgerald P. M., Vacca J. P., Dorsey B. D., Levin R. B., Thompson W. J., Chen L. J., deSolms S. J. A priori prediction of activity for HIV-1 protease inhibitors employing energy minimization in the active site. J Med Chem. 1995 Jan 20;38(2):305–317. doi: 10.1021/jm00002a012. [DOI] [PubMed] [Google Scholar]
  43. Horton N., Lewis M. Calculation of the free energy of association for protein complexes. Protein Sci. 1992 Jan;1(1):169–181. doi: 10.1002/pro.5560010117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Huff J. R. HIV protease: a novel chemotherapeutic target for AIDS. J Med Chem. 1991 Aug;34(8):2305–2314. doi: 10.1021/jm00112a001. [DOI] [PubMed] [Google Scholar]
  45. Hutchins C., Greer J. Comparative modeling of proteins in the design of novel renin inhibitors. Crit Rev Biochem Mol Biol. 1991;26(1):77–127. doi: 10.3109/10409239109081721. [DOI] [PubMed] [Google Scholar]
  46. Janin J., Chothia C. The structure of protein-protein recognition sites. J Biol Chem. 1990 Sep 25;265(27):16027–16030. [PubMed] [Google Scholar]
  47. Jaskólski M., Tomasselli A. G., Sawyer T. K., Staples D. G., Heinrikson R. L., Schneider J., Kent S. B., Wlodawer A. Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor. Biochemistry. 1991 Feb 12;30(6):1600–1609. doi: 10.1021/bi00220a023. [DOI] [PubMed] [Google Scholar]
  48. Jenny T. F., Gerloff D. L., Cohen M. A., Benner S. A. Predicted secondary and supersecondary structure for the serine-threonine-specific protein phosphatase family. Proteins. 1995 Jan;21(1):1–10. doi: 10.1002/prot.340210102. [DOI] [PubMed] [Google Scholar]
  49. Jorgensen W. L. Rusting of the lock and key model for protein-ligand binding. Science. 1991 Nov 15;254(5034):954–955. doi: 10.1126/science.1719636. [DOI] [PubMed] [Google Scholar]
  50. KAUZMANN W. Some factors in the interpretation of protein denaturation. Adv Protein Chem. 1959;14:1–63. doi: 10.1016/s0065-3233(08)60608-7. [DOI] [PubMed] [Google Scholar]
  51. Kabsch W., Sander C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 1983 Dec;22(12):2577–2637. doi: 10.1002/bip.360221211. [DOI] [PubMed] [Google Scholar]
  52. King R. D., Sternberg M. J. Machine learning approach for the prediction of protein secondary structure. J Mol Biol. 1990 Nov 20;216(2):441–457. doi: 10.1016/S0022-2836(05)80333-X. [DOI] [PubMed] [Google Scholar]
  53. Komine S., Yoshida K., Yamashita H., Masaki Z. Voiding dysfunction in patients with human T-lymphotropic virus type-1-associated myelopathy (HAM). Paraplegia. 1989 Jun;27(3):217–221. doi: 10.1038/sc.1989.32. [DOI] [PubMed] [Google Scholar]
  54. Lam P. Y., Jadhav P. K., Eyermann C. J., Hodge C. N., Ru Y., Bacheler L. T., Meek J. L., Otto M. J., Rayner M. M., Wong Y. N. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science. 1994 Jan 21;263(5145):380–384. doi: 10.1126/science.8278812. [DOI] [PubMed] [Google Scholar]
  55. Lawrence M. C., Colman P. M. Shape complementarity at protein/protein interfaces. J Mol Biol. 1993 Dec 20;234(4):946–950. doi: 10.1006/jmbi.1993.1648. [DOI] [PubMed] [Google Scholar]
  56. Lee B., Richards F. M. The interpretation of protein structures: estimation of static accessibility. J Mol Biol. 1971 Feb 14;55(3):379–400. doi: 10.1016/0022-2836(71)90324-x. [DOI] [PubMed] [Google Scholar]
  57. Levin J. M., Garnier J. Improvements in a secondary structure prediction method based on a search for local sequence homologies and its use as a model building tool. Biochim Biophys Acta. 1988 Aug 10;955(3):283–295. doi: 10.1016/0167-4838(88)90206-3. [DOI] [PubMed] [Google Scholar]
  58. Levin J. M., Pascarella S., Argos P., Garnier J. Quantification of secondary structure prediction improvement using multiple alignments. Protein Eng. 1993 Nov;6(8):849–854. doi: 10.1093/protein/6.8.849. [DOI] [PubMed] [Google Scholar]
  59. Lunney E. A., Hagen S. E., Domagala J. M., Humblet C., Kosinski J., Tait B. D., Warmus J. S., Wilson M., Ferguson D., Hupe D. A novel nonpeptide HIV-1 protease inhibitor: elucidation of the binding mode and its application in the design of related analogs. J Med Chem. 1994 Aug 19;37(17):2664–2677. doi: 10.1021/jm00043a006. [DOI] [PubMed] [Google Scholar]
  60. Magalhaes A., Maigret B., Hoflack J., Gomes J. N., Scheraga H. A. Contribution of unusual arginine-arginine short-range interactions to stabilization and recognition in proteins. J Protein Chem. 1994 Feb;13(2):195–215. doi: 10.1007/BF01891978. [DOI] [PubMed] [Google Scholar]
  61. Makhatadze G. I., Privalov P. L. Contribution of hydration to protein folding thermodynamics. I. The enthalpy of hydration. J Mol Biol. 1993 Jul 20;232(2):639–659. doi: 10.1006/jmbi.1993.1416. [DOI] [PubMed] [Google Scholar]
  62. Makhatadze G. I., Privalov P. L. Heat capacity of proteins. I. Partial molar heat capacity of individual amino acid residues in aqueous solution: hydration effect. J Mol Biol. 1990 May 20;213(2):375–384. doi: 10.1016/S0022-2836(05)80197-4. [DOI] [PubMed] [Google Scholar]
  63. Mark A. E., van Gunsteren W. F. Decomposition of the free energy of a system in terms of specific interactions. Implications for theoretical and experimental studies. J Mol Biol. 1994 Jul 8;240(2):167–176. doi: 10.1006/jmbi.1994.1430. [DOI] [PubMed] [Google Scholar]
  64. McCarrick M. A., Kollman P. Use of molecular dynamics and free energy perturbation calculations in anti-human immunodeficiency virus drug design. Methods Enzymol. 1994;241:370–384. doi: 10.1016/0076-6879(94)41074-7. [DOI] [PubMed] [Google Scholar]
  65. Miller S. The structure of interfaces between subunits of dimeric and tetrameric proteins. Protein Eng. 1989 Nov;3(2):77–83. doi: 10.1093/protein/3.2.77. [DOI] [PubMed] [Google Scholar]
  66. Miyazawa S., Jernigan R. L. A new substitution matrix for protein sequence searches based on contact frequencies in protein structures. Protein Eng. 1993 Apr;6(3):267–278. doi: 10.1093/protein/6.3.267. [DOI] [PubMed] [Google Scholar]
  67. Moon J. B., Howe W. J. Computer design of bioactive molecules: a method for receptor-based de novo ligand design. Proteins. 1991;11(4):314–328. doi: 10.1002/prot.340110409. [DOI] [PubMed] [Google Scholar]
  68. Murphy K. P., Xie D., Thompson K. S., Amzel L. M., Freire E. Entropy in biological binding processes: estimation of translational entropy loss. Proteins. 1994 Jan;18(1):63–67. doi: 10.1002/prot.340180108. [DOI] [PubMed] [Google Scholar]
  69. Nicholls A., Sharp K. A., Honig B. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins. 1991;11(4):281–296. doi: 10.1002/prot.340110407. [DOI] [PubMed] [Google Scholar]
  70. Némethy G. Hydrophobic interactions. Angew Chem Int Ed Engl. 1967 Mar;6(3):195–206. doi: 10.1002/anie.196701951. [DOI] [PubMed] [Google Scholar]
  71. Ooi T., Oobatake M., Némethy G., Scheraga H. A. Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides. Proc Natl Acad Sci U S A. 1987 May;84(10):3086–3090. doi: 10.1073/pnas.84.10.3086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Oprea T. I., Waller C. L., Marshall G. R. Three-dimensional quantitative structure-activity relationship of human immunodeficiency virus (I) protease inhibitors. 2. Predictive power using limited exploration of alternate binding modes. J Med Chem. 1994 Jul 8;37(14):2206–2215. doi: 10.1021/jm00040a013. [DOI] [PubMed] [Google Scholar]
  73. Otting G., Liepinsh E., Wüthrich K. Protein hydration in aqueous solution. Science. 1991 Nov 15;254(5034):974–980. doi: 10.1126/science.1948083. [DOI] [PubMed] [Google Scholar]
  74. Otto M. J., Garber S., Winslow D. L., Reid C. D., Aldrich P., Jadhav P. K., Patterson C. E., Hodge C. N., Cheng Y. S. In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7543–7547. doi: 10.1073/pnas.90.16.7543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Poorman R. A., Tomasselli A. G., Heinrikson R. L., Kézdy F. J. A cumulative specificity model for proteases from human immunodeficiency virus types 1 and 2, inferred from statistical analysis of an extended substrate data base. J Biol Chem. 1991 Aug 5;266(22):14554–14561. [PubMed] [Google Scholar]
  76. Privalov P. L., Makhatadze G. I. Contribution of hydration and non-covalent interactions to the heat capacity effect on protein unfolding. J Mol Biol. 1992 Apr 5;224(3):715–723. doi: 10.1016/0022-2836(92)90555-x. [DOI] [PubMed] [Google Scholar]
  77. Privalov P. L., Makhatadze G. I. Contribution of hydration to protein folding thermodynamics. II. The entropy and Gibbs energy of hydration. J Mol Biol. 1993 Jul 20;232(2):660–679. doi: 10.1006/jmbi.1993.1417. [DOI] [PubMed] [Google Scholar]
  78. Privalov P. L., Makhatadze G. I. Heat capacity of proteins. II. Partial molar heat capacity of the unfolded polypeptide chain of proteins: protein unfolding effects. J Mol Biol. 1990 May 20;213(2):385–391. doi: 10.1016/S0022-2836(05)80198-6. [DOI] [PubMed] [Google Scholar]
  79. Reddy M. R., Varney M. D., Kalish V., Viswanadhan V. N., Appelt K. Calculation of relative differences in the binding free energies of HIV1 protease inhibitors: a thermodynamic cycle perturbation approach. J Med Chem. 1994 Apr 15;37(8):1145–1152. doi: 10.1021/jm00034a012. [DOI] [PubMed] [Google Scholar]
  80. Rich D. H., Sun C. Q., Vara Prasad J. V., Pathiasseril A., Toth M. V., Marshall G. R., Clare M., Mueller R. A., Houseman K. Effect of hydroxyl group configuration in hydroxyethylamine dipeptide isosteres on HIV protease inhibition. Evidence for multiple binding modes. J Med Chem. 1991 Mar;34(3):1222–1225. doi: 10.1021/jm00107a049. [DOI] [PubMed] [Google Scholar]
  81. Richards F. M. Areas, volumes, packing and protein structure. Annu Rev Biophys Bioeng. 1977;6:151–176. doi: 10.1146/annurev.bb.06.060177.001055. [DOI] [PubMed] [Google Scholar]
  82. Richmond T. J. Solvent accessible surface area and excluded volume in proteins. Analytical equations for overlapping spheres and implications for the hydrophobic effect. J Mol Biol. 1984 Sep 5;178(1):63–89. doi: 10.1016/0022-2836(84)90231-6. [DOI] [PubMed] [Google Scholar]
  83. Ripoll D. R., Faerman C. H., Axelsen P. H., Silman I., Sussman J. L. An electrostatic mechanism for substrate guidance down the aromatic gorge of acetylcholinesterase. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5128–5132. doi: 10.1073/pnas.90.11.5128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Rose G. D., Geselowitz A. R., Lesser G. J., Lee R. H., Zehfus M. H. Hydrophobicity of amino acid residues in globular proteins. Science. 1985 Aug 30;229(4716):834–838. doi: 10.1126/science.4023714. [DOI] [PubMed] [Google Scholar]
  85. Roseman M. A. Hydrophilicity of polar amino acid side-chains is markedly reduced by flanking peptide bonds. J Mol Biol. 1988 Apr 5;200(3):513–522. doi: 10.1016/0022-2836(88)90540-2. [DOI] [PubMed] [Google Scholar]
  86. Rost B., Sander C. Combining evolutionary information and neural networks to predict protein secondary structure. Proteins. 1994 May;19(1):55–72. doi: 10.1002/prot.340190108. [DOI] [PubMed] [Google Scholar]
  87. Rost B., Sander C. Prediction of protein secondary structure at better than 70% accuracy. J Mol Biol. 1993 Jul 20;232(2):584–599. doi: 10.1006/jmbi.1993.1413. [DOI] [PubMed] [Google Scholar]
  88. Rost B., Sander C., Schneider R. PHD--an automatic mail server for protein secondary structure prediction. Comput Appl Biosci. 1994 Feb;10(1):53–60. doi: 10.1093/bioinformatics/10.1.53. [DOI] [PubMed] [Google Scholar]
  89. Salamov A. A., Solovyev V. V. Prediction of protein secondary structure by combining nearest-neighbor algorithms and multiple sequence alignments. J Mol Biol. 1995 Mar 17;247(1):11–15. doi: 10.1006/jmbi.1994.0116. [DOI] [PubMed] [Google Scholar]
  90. Salzberg S., Cost S. Predicting protein secondary structure with a nearest-neighbor algorithm. J Mol Biol. 1992 Sep 20;227(2):371–374. doi: 10.1016/0022-2836(92)90892-n. [DOI] [PubMed] [Google Scholar]
  91. Sander C., Schneider R. Database of homology-derived protein structures and the structural meaning of sequence alignment. Proteins. 1991;9(1):56–68. doi: 10.1002/prot.340090107. [DOI] [PubMed] [Google Scholar]
  92. Sawyer T. K., Staples D. J., Liu L., Tomasselli A. G., Hui J. O., O'Connell K., Schostarez H., Hester J. B., Moon J., Howe W. J. HIV protease (HIV PR) inhibitor structure-activity-selectivity, and active site molecular modeling of high affinity Leu [CH(OH)CH2]Val modified viral and nonviral substrate analogs. Int J Pept Protein Res. 1992 Sep-Oct;40(3-4):274–281. doi: 10.1111/j.1399-3011.1992.tb00302.x. [DOI] [PubMed] [Google Scholar]
  93. Sharp K. A., Nicholls A., Fine R. F., Honig B. Reconciling the magnitude of the microscopic and macroscopic hydrophobic effects. Science. 1991 Apr 5;252(5002):106–109. doi: 10.1126/science.2011744. [DOI] [PubMed] [Google Scholar]
  94. Shi Y. Y., Mark A. E., Wang C. X., Huang F., Berendsen H. J., van Gunsteren W. F. Can the stability of protein mutants be predicted by free energy calculations? Protein Eng. 1993 Apr;6(3):289–295. doi: 10.1093/protein/6.3.289. [DOI] [PubMed] [Google Scholar]
  95. Shirley B. A., Stanssens P., Hahn U., Pace C. N. Contribution of hydrogen bonding to the conformational stability of ribonuclease T1. Biochemistry. 1992 Jan 28;31(3):725–732. doi: 10.1021/bi00118a013. [DOI] [PubMed] [Google Scholar]
  96. Sippl M. J. Boltzmann's principle, knowledge-based mean fields and protein folding. An approach to the computational determination of protein structures. J Comput Aided Mol Des. 1993 Aug;7(4):473–501. doi: 10.1007/BF02337562. [DOI] [PubMed] [Google Scholar]
  97. Srivastava S., Crippen G. M. Analysis of cocaine receptor site ligand binding by three-dimensional Voronoi site modeling approach. J Med Chem. 1993 Nov 12;36(23):3572–3579. doi: 10.1021/jm00075a012. [DOI] [PubMed] [Google Scholar]
  98. Stolorz P., Lapedes A., Xia Y. Predicting protein secondary structure using neural net and statistical methods. J Mol Biol. 1992 May 20;225(2):363–377. doi: 10.1016/0022-2836(92)90927-c. [DOI] [PubMed] [Google Scholar]
  99. Swain A. L., Miller M. M., Green J., Rich D. H., Schneider J., Kent S. B., Wlodawer A. X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8805–8809. doi: 10.1073/pnas.87.22.8805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Thanki N., Rao J. K., Foundling S. I., Howe W. J., Moon J. B., Hui J. O., Tomasselli A. G., Heinrikson R. L., Thaisrivongs S., Wlodawer A. Crystal structure of a complex of HIV-1 protease with a dihydroxyethylene-containing inhibitor: comparisons with molecular modeling. Protein Sci. 1992 Aug;1(8):1061–1072. doi: 10.1002/pro.5560010811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Thompson S. K., Murthy K. H., Zhao B., Winborne E., Green D. W., Fisher S. M., DesJarlais R. L., Tomaszek T. A., Jr, Meek T. D., Gleason J. G. Rational design, synthesis, and crystallographic analysis of a hydroxyethylene-based HIV-1 protease inhibitor containing a heterocyclic P1'--P2' amide bond isostere. J Med Chem. 1994 Sep 16;37(19):3100–3107. doi: 10.1021/jm00045a015. [DOI] [PubMed] [Google Scholar]
  102. Tuñn I., Silla E., Pascual-Ahuir J. L. Molecular surface area and hydrophobic effect. Protein Eng. 1992 Dec;5(8):715–716. doi: 10.1093/protein/5.8.715. [DOI] [PubMed] [Google Scholar]
  103. Varney M. D., Appelt K., Kalish V., Reddy M. R., Tatlock J., Palmer C. L., Romines W. H., Wu B. W., Musick L. Crystal-structure-based design and synthesis of novel C-terminal inhibitors of HIV protease. J Med Chem. 1994 Jul 22;37(15):2274–2284. doi: 10.1021/jm00041a005. [DOI] [PubMed] [Google Scholar]
  104. Verdonk M. L., Boks G. J., Kooijman H., Kanters J. A., Kroon J. Stereochemistry of charged nitrogen-aromatic interactions and its involvement in ligand-receptor binding. J Comput Aided Mol Des. 1993 Apr;7(2):173–182. doi: 10.1007/BF00126443. [DOI] [PubMed] [Google Scholar]
  105. Verlinde C. L., Hol W. G. Structure-based drug design: progress, results and challenges. Structure. 1994 Jul 15;2(7):577–587. doi: 10.1016/s0969-2126(00)00060-5. [DOI] [PubMed] [Google Scholar]
  106. Vincent J. P., Lazdunski M. Trypsin-pancreatic trypsin inhibitor association. Dynamics of the interaction and role of disulfide bridges. Biochemistry. 1972 Aug 1;11(16):2967–2977. doi: 10.1021/bi00766a007. [DOI] [PubMed] [Google Scholar]
  107. Vincent J. P., Peron-Renner M., Pudles J., Lazdunski M. The association of anhydrotrypsin with the pancreatic trypsin inhibitors. Biochemistry. 1974 Sep 24;13(20):4205–4211. doi: 10.1021/bi00717a023. [DOI] [PubMed] [Google Scholar]
  108. Walls P. H., Sternberg M. J. New algorithm to model protein-protein recognition based on surface complementarity. Applications to antibody-antigen docking. J Mol Biol. 1992 Nov 5;228(1):277–297. doi: 10.1016/0022-2836(92)90506-f. [DOI] [PubMed] [Google Scholar]
  109. Walshaw J., Goodfellow J. M. Distribution of solvent molecules around apolar side-chains in protein crystals. J Mol Biol. 1993 May 20;231(2):392–414. doi: 10.1006/jmbi.1993.1290. [DOI] [PubMed] [Google Scholar]
  110. Wodak S. J., Janin J. Computer analysis of protein-protein interaction. J Mol Biol. 1978 Sep 15;124(2):323–342. doi: 10.1016/0022-2836(78)90302-9. [DOI] [PubMed] [Google Scholar]
  111. Young L., Jernigan R. L., Covell D. G. A role for surface hydrophobicity in protein-protein recognition. Protein Sci. 1994 May;3(5):717–729. doi: 10.1002/pro.5560030501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Zhang X., Mesirov J. P., Waltz D. L. Hybrid system for protein secondary structure prediction. J Mol Biol. 1992 Jun 20;225(4):1049–1063. doi: 10.1016/0022-2836(92)90104-r. [DOI] [PubMed] [Google Scholar]
  113. Zvelebil M. J., Barton G. J., Taylor W. R., Sternberg M. J. Prediction of protein secondary structure and active sites using the alignment of homologous sequences. J Mol Biol. 1987 Jun 20;195(4):957–961. doi: 10.1016/0022-2836(87)90501-8. [DOI] [PubMed] [Google Scholar]

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