Atypical protonation states in the active site of HIV-1 protease: A computational study

Journal of Chemical Information and Modeling

Volumn 47, Issue 4, 2007, Pages 1590-1598

  Czodrowski, Paul ^a   Sotriffer, Christoph A ^a   Klebe, Gerhard ^a  

^a PHILIPPS UNIVERSITY MARBURG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

BINDING ENERGY; COMPUTATIONAL METHODS; DRUG PRODUCTS; MOLECULAR MODELING; PROTONATION;

ACTIVE SITE; LIGAND BINDING; PROTONATION STATES;

ENZYMES;

PROTEINASE; PROTEINASE INHIBITOR; PROTON;

ARTICLE; BINDING SITE; CHEMICAL STRUCTURE; CHEMISTRY;

BINDING SITES; HIV PROTEASE; HIV PROTEASE INHIBITORS; MODELS, MOLECULAR; PROTONS;

EID: 34547657456     PISSN: 15499596     EISSN: 1549960X     Source Type: Journal    
DOI: 10.1021/ci600522c     Document Type: Article

References (28)

1. Coffin, J.; Haase, A.; Levy, J. A.; Montagnier, L.; Oroszlan, S.; Teich, N.; Temin, H.; Toyoshima, L.; Varmus, H.; Vorgt, P.; Weiss, R. Human Immunodeficiency Virus. Science 1986, 232, 697-700.
2. Hyland, L. J.; Tomaszek, T. A.; Meek, T. D. Human immunodeficiency virus-1 protease. 2. Use of pH rate studies and solvent kinetic isotope effects to elucidate details of chemical mechanism. Biochemistry 1991, 30, 8454-8463.
3. Ido, E.; Han, H.; Kezdy, F. J.; Tang, J. Kinetic studies of Human Immunodeficiency Virus type 1 protease and its active-site hydrogen bond mutant A28S. J. Biol. Chem. 1991, 266, 24349-24366.
4. Yamazaki, T.; Nicholson, K.; Torchia, D. A.; Wingfield, P.; Stahl, S. J.; Kaufman, J. D.; Eyerman, C. J.; Hodge, C. N.; Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Chang, C.; Weber, P. C NMR and X-ray evidence that the HTV-1 protease catalytic aspartyl groups are protonated in the complex formed by the protease and a non-peptide cyclic ureabased inhibitor. J. Am. Chem. Soc. 1994, 116, 10791-10792.
5. Wang, Y. X.; Freedberg, D. I.; Yamazaki, T.; Wingfield, P. T.; Stahl, S. J.; Kaufman, D.; Kiso, Y.; Torchia, D. A. Solution NMR evidence that the HTV-1 protease catalytic aspartyl groups have different ionization states in the complex formed with the asymmetric drug KNI-272. Biochemistry 1996, 35, 9945-9950.
6. Czodrowski, P.; Dramburg, I.; Sotriffer, C A.; Klebe, G. Development, Validation, and Application of Adapted PEOE Charges to Estimate pKa Values of Functional Groups in Protein-Ligand Complexes. Proteins 2006, 65, 424-437.
7. Trylska, J.; Antosiewicz, J.; Geller, M.; Hodge, C. N.; Klabe, R. M.; Head, M. S.; Gilson, M. K. Thermodynamic linkage between the binding of protons and inhibitors to HTV-I protease. Protein Sci. 1999, 5, 180-195.
8. Schutz, C. N.; Warshel, A. What are the Dielectric "Constants" of Proteins and How To Validate Electrostatic Models? Proteins 2001, 44, 400-417.
9. Antosiewicz, J.; McCammon, J. A.; Gilson, M. K. Prediction of pH-dependent properties of proteins. J. Mol. Biol. 1994, 238, 415-436.
10. Demchuk, E.; Wade, R. C Improving the continuum dielectric approach to calculating pKas of ionizable groups in proteins. J. Phys. Chem. 1996, 100, 17373-17387.
11. Nielsen, J. E.; McCammon, J. A. Calculating pKa values in enzyme active sites. Protein Sci. 2003, 12, 1894-1901.
12. Joshi, M. D.; Sidhu, G.; Nielsen, J. E.; Brayer, G. D.; Withers, S. G.; Mcintosh, L. P. Dissecting the electrostatic interactions and pH-dependent activity of a family 11 glycosidase. Biochemistry 2001, 40, 10115-10139.
13. King, G.; Lee, F. S.; Warshel, A. Microscopic simulations of macroscopic dielectric constants of solvated proteins. J. Chem. Phys. 1991, 95, 4366-4377.
14. Bashford, D. In An object-oriented programming suite for electrostatic effects in biological molecules; Scientific computing in object-oriented parallel environments, 1997; Ishikawa, Y., Oldehoeft, R. R., Reynders, J. V. W., Tholburn, M., Eds.; Springer: Berlin, ISCOPE97: 1997; pp 233-240.
15. Dolinsky, T. J.; Nielsen, J. E.; McCammon, J. A.; Baker, N. A. PDB2PQR: an automated pipeline for the setup, execution, and analysis of Poisson-Boltzmann electrostatics calculations. Nucleic Acids Res. 2004, 32, 665-667.
16. SYBYL 7.0; Tripos Inc.: St. Louis, MO, 2002.
17. Smith, R.; Breton, I. M.; Chai, R. Y.; Kent, S. B. H. Ionization states of the catalytic residues in HTV-1 protease. Nat. Struct. Biol. 1997, 3, 946-950.
18. Antosiewicz, J.; McCammon, J. A.; Gilson, M. K. The determinants of pKas in proteins. Biochemistry 1996, 35, 7819-7833.
19. Lam, P. Y.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; DeLucca, G. V.; Eyermann, C J.; Chang, C H.; Emmett, G.; Holler, E. R.; Daneker, W. F.; Li, L.; Confalone, P. N.; McHugh, R. J.; Han, Q.; Li, R.; Markwalder, J. A.; Seitz, S. P.; Sharpe, T. R.; Bacheler, L. T.; Rayner, M. M.; Klabe, R. M.; Shum, L.; Winslow, D. L.; Kornhauser, D. M.; Hodge, C. N. Cyclic HTV protease inhibitors: synthesis, conformational analysis, P2/P2′ structure-activity relationship, and molecular recognition of cyclic ureas. J. Med. Chem. 1996, 39, 3514-3525.
20. Ishima, R.; Freedberg, D. I.; Wang, Y. X.; Louis, J. M.; Torchia, D. A.; Tung, R. D.; Navia, M. A. Flap opening and dimer-interface flexibility in the free and inhibitor-bound HIV protease, and their implications for function. Structure 1999, 7, 1047-1055.
21. Czodrowski, P.; Sotriffer, C. A.; Klebe, G. Protonation changes upon ligand binding to trypsin and thrombin: Structural interpretation based on pKa calculations and TTC experiments. J. Mol. Biol. 2007, 367, 1347-1356.
22. Mimoto, T.; Kiso, Y. Kynostatin (KNI)-227 and 272, highly potent anti-HIV agents: conformationally-constrained tripeptide inhibitors of HIV protease containing allophenylnorstatine. Chem. Pharm. Bull. 1992, 40, 2251-2253.
23. Baldwin, E. T.; Bhat, N.; Gulnik, S.; Liu, B.; Topol, I. A.; Kiso, Y.; Mimoto, T.; Mitsuya, H.; Erickson, J. W. Structure of HTV-1 protease with KNI-272, a tight-binding transition-state analog containing allophenylnorstatine. Structure 1995, 3, 581-590.
24. Specker, E.; Böttcher, J.; Brass, S.; Heine, A.; Lilie, H.; Schoop, A.; Müller, G.; Griebenow, N.; Klebe, G. Unexpected novel binding mode of pyrrolidine-based aspartyl protease inhibitors: design, synthesis and crystal structure of HIV protease. ChemMedChem. 2006, 1, 106-117.
25. Specker, E.; Böttcher, J.; Heine, A.; Sotriffer, C. A.; Lilie, H.; Schoop, A.; Müller, G.; Griebenow, N.; Klebe, G. Hydroxyethylene sulfones as new scaffold to address aspartic proteases: design, synthesis and structural classification. J. Med. Chem. 2005, 48, 6607-6619.
26. Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Murcko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. A. Crystal structure of HTV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme. J. Am. Chem. Soc. 1995, 117, 1181-1182.
27. Cabani, S.; Conti, G.; Lepori, L. Thermodynamic study on aqueous dilute solutions of organic compounds. Trans. Faraday Soc. 1971, 67, 1933-1942.
28. Harte, W. E.; Beveridge, D. L. Prediction of the Protonation States of the Active Site Aspartyl Residues in HTV-I Protease-Inhibitor Complexes via Molecular Dynamics Simulation. J. Am. Chem. Soc. 1993, 115, 3883-3886.