Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

Investigation of the Protonated State of HIV-1 Protease Active Site

  • Nam, Ky-Youb (Department of Chemistry and CAMD Research Center, Soongsil University) ;
  • Chang, Byung-Ha (Department of Chemistry and CAMD Research Center, Soongsil University) ;
  • Han, Cheol-Kyu (Department of Chemistry and CAMD Research Center, Soongsil University) ;
  • Ahn, Soon-Kil (Chong Kun Dang Research Institute) ;
  • No, Kyoung-Tai (Department of Biotechnology, Yonsei University)
  • Published : 2003.06.20
Download PDF
⟨ Previous Next ⟩

Abstract

We have performed ab initio calculation on the active site of HIV-1 protease. The FEP method was used to determine the binding free energy of four different of protonated states of HIV-1 protease with inhibitor. The structure of the active site and hole structure was taken from the X-ray crystallographic coordinates of the C₂ symmetric inhibitor A74704 protease bound. The active site was modeled with the fragment molecules of binding pocket, acetic acid/ acetate anion (Asp25, Asp125), formamide (amide bond of Thr26/Gly27, Thr126/ Gly127), and methanol as inhibitor fragment. All possibly protonated states of the active site were considered, which were diprotonated state (0, 0), monoprotonated (-1, 0),(0, -1) and diunprotonated state (-1, -1). Once the binding energy Debind, of each model was calculated, more probabilistic protonated states can be proposed from binding energy. From ab-initio results, the FEP simulations were performed for the three following mutations: Ⅰ) Asp25 … Asp125 → AspH25 … Asp125, ⅱ) Asp25 … Asp125 → Asp25 … AspH125, ⅲ) AspH25 … Asp125 → AspH25 … AspH125. The free energy difference between the four states gives the information of the more realistic protonated state of active site aspartic acid. These results provide a theoretical prediction of the protonation state of the catalytic aspartic residues for A74707 complex, and may be useful for the evaluation of potential therapeutic targets.

Keywords

References

  1. Mitsuya, H.; Yarchoan, R.; Broder, S. Science 1990, 249, 1533-1544. https://doi.org/10.1126/science.1699273
  2. Debouck, C. Aids Rearch and Human Retroviruses 1992, 8, 153-164. https://doi.org/10.1089/aid.1992.8.153
  3. Kohl, N. E.; Emini, E. A.; Schleif, W. A.; Davis, L. I.; Heimbach,J. C.; Dixon, R. A.; Scolnick, E. M.; Sigal, I. S. Proc. Natl. Acad.Sci. U.S.A. 1988, 85, 4686-4690. https://doi.org/10.1073/pnas.85.13.4686
  4. Miller, M.; Schneider, J.; Sathyanarayana, B. M.; Toth, M. V.;Marshall, G. R.; Clawson, L.; Selk, L.; Kent, S. B. H.; Wlodawer,A. Science 1989, 246, 1149-1151. https://doi.org/10.1126/science.2686029
  5. Swain, A. L.; Miller, M.; Green, J.; Rich, D. H.; Schneider, J.;Kent, S. B. H.; Wlodawer, A. Proc. Natl. Acad. Sci. U. S. A. 1990,87, 8850-8809.
  6. Jaskolski, M.; Tomasselli, A. G.; Sawyer, T. K.; Staples, D. G.;Heinrikson, R. L.; Schneider, J.; Kent, S. B. H.; Wlodawer, A.Biochemistry 1991, 30, 1600-1609. https://doi.org/10.1021/bi00220a023
  7. Fitzgerald, P. M. D.; McKeever, B. M.; VanMiddleworth, J. F.;Springer, J. P.; Heimbach, J. C.; Leu, C.; Herbert, W. K.; Dixon, R.A. F.; Darke, P. L. J. Bio. Chem. 1990, 265, 14209-14219.
  8. Erikson, J.; Neidhart, D. J.; VanDrie, J.; Kempf, D. J.; Wang, X.C.; Norbeck, D. W.; Plattner, J. J.; Rittenhouse, J. W.; Turon, M.;Widenburg, N.; Kohlbrenner, W. E.; Simmer, R.; Helfrich, R.;Paul, D. A.; Kingge, M. Science 1990, 249, 527-533. https://doi.org/10.1126/science.2200122
  9. James, M. N. G.; Salituro, F. S.; Rich, H. D.; Hofmann, T. Proc.Natl. Acad. Sci. U. S. A. 1982, 79, 6137. https://doi.org/10.1073/pnas.79.20.6137
  10. Schechter, I.; Berger, A. Biochem. Biophys. Res. Comun. 1967,27, 157-162. https://doi.org/10.1016/S0006-291X(67)80055-X
  11. Hyland, L. J.; Tomaszek, T. A., Jr.; Roberts, G. D.; Carr, S. A.;Magaard, V. W.; Bryan, H. L.; Fakhoury, S. A.; Moore, M. L.;Minnich, M. D.; Culp, J. S.; DesJarlis, R. L.; Meek, T. D.Biochemistry 1991, 30, 8441-8453. https://doi.org/10.1021/bi00098a023
  12. Hyland, L. J.; Tomaszek, T. A., Jr.; Meek, T. D. Biochemistry1991, 30, 8454-8463. https://doi.org/10.1021/bi00098a024
  13. Rodriguez, E. J.; Angeles, T. S.; Meek, T. D. Biochemistry 1993,32, 12380-12385. https://doi.org/10.1021/bi00097a015
  14. Harte, W. E., Jr.; Beverage, D. L. J. Am. Chem. Soc. 1993, 115,3883-3886. https://doi.org/10.1021/ja00063a005
  15. Chen, X.; Tropsha, A. J. Med. Chem. 1995, 38, 42-48. https://doi.org/10.1021/jm00001a009
  16. Ferguson, D. M.; Radmer, R. J.; Kollman, P. A. J. Med. Chem.1991, 34, 2564-2569.
  17. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.; Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T. A.;Petersson, G. A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J. V.; Foresman, J. B.;Peng, C. Y.; Ayala, P. A.; Wong, M. W.; Andres, J. L.; Replogle, E.S.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Binkley, J. S.; Defrees,D. J.; Baker, J.; Stewart, J. P.; Head-Gordon, M.; Gonzalez, C.;and Pople, J. A. Gaussian 94 (Revision D.3); Gaussian, Inc.:Pittsburgh, PA, 1995.
  18. Keith, T. A.; Foresman, J. B.; Frisch, M. J.; Weiberg, K. B.manuscript in preparation.
  19. Foresman, J. B.; Keith, T. A.; Weiberg, K. B.; Frisch, M. J. J.Phys. Chem. 1996, 100, 16098-16104. https://doi.org/10.1021/jp960488j
  20. Mezei, M. J. Chem. Phys. 1987, 86, 7084-7088. https://doi.org/10.1063/1.452357
  21. Molecular dynamic simulation was performed using the InsightII/Discover (2.9.5). MSI Inc.: InsightII (950)/Discover 2.9.5Molecular Modeling Software; San Diego, CA, 1995.
  22. Hagler, A. T.; Lifson, S.; Dauber, P. J. Am. Chem. Soc. 1979, 101,5122-5130. https://doi.org/10.1021/ja00512a002
  23. Lifson, S.; Hagler, A. T.; Dauber, P. J. Am. Chem. Soc. 1979, 101,5131. https://doi.org/10.1021/ja00512a003
  24. Fixed geometry were used of HIV-1 protease in which fixedamino acid residues were listed, 1-7, 11-21, 34-46, 55-75, 89-99,101-107, 111-121, 134-146, 155-175 and 189-199.
  25. No, K. T.; Kwon, O. Y.; Kim, S. Y.; Jhon, M. S.; Scheraga, A. H. J.Phys. Chem. 1995, 99, 3478. https://doi.org/10.1021/j100011a013
  26. Wang, Y.-X.; Freedberg, I. D.; Yamazaki, T.; Wingfield, T. P.;Stahl, J. S.; Kaufman, D. J.; Kiso, Y.; Torchia, A. D. Biochemistry1996, 31, 9945-9950.
  27. Baldwin, E. T.; Bhat, T. N.; Gulnik, S.; Liu, B.; Topol, I. A.; Kiso,Y.; Mimoto, T.; Mitsuya, H.; Erickson, J. W. Structure 1995, 3,581-590. https://doi.org/10.1016/S0969-2126(01)00192-7
  28. Won, Y. Bull. Korean Chem. Soc. 2000, 21, 1207-1212.
  29. Won, H.; Kim, J. R.; Ko, K.; Won, Y. Bull. Korean Chem. Soc.2003, 23, 27-28.

Cited by

  1. Ion specific effects of alkali cations on the catalytic activity of HIV-1 protease vol.160, pp.1364-5498, 2013, https://doi.org/10.1039/C2FD20094E
  2. Protonation state and free energy calculation of HIV-1 protease–inhibitor complex based on electrostatic polarisation effect vol.112, pp.12, 2014, https://doi.org/10.1080/00268976.2013.857050
  3. pH-REMD Simulations Indicate That the Catalytic Aspartates of HIV-1 Protease Exist Primarily in a Monoprotonated State vol.118, pp.44, 2014, https://doi.org/10.1021/jp504011c
  4. Accurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitors vol.29, pp.5, 2008, https://doi.org/10.1002/jcc.20821
  5. Drug-resistant molecular mechanism of CRF01_AE HIV-1 protease due to V82F mutation vol.23, pp.5, 2009, https://doi.org/10.1007/s10822-008-9256-x
  6. Ion specific effects of sodium and potassium on the catalytic activity of HIV-1 protease vol.11, pp.35, 2009, https://doi.org/10.1039/b905462f
  7. Blind docking of 260 protein-ligand complexes with EADock 2.0 vol.30, pp.13, 2009, https://doi.org/10.1002/jcc.21202
  8. Structural and dynamical properties of different protonated states of mutant HIV-1 protease complexed with the saquinavir inhibitor studied by molecular dynamics simulations vol.25, pp.3, 2003, https://doi.org/10.1016/j.jmgm.2006.01.004
  9. Physical Chemistry Research Articles Published in the Bulletin of the Korean Chemical Society: 2003-2007 vol.29, pp.2, 2008, https://doi.org/10.5012/bkcs.2008.29.2.450
  10. Prediction of Relative Stability between TACE/Gelastatin and TACE/Gelastatin Hydroxamate vol.31, pp.11, 2003, https://doi.org/10.5012/bkcs.2010.31.11.3291
  11. Performance of radial distribution function-based descriptors in the chemoinformatic studies of HIV-1 protease vol.12, pp.4, 2003, https://doi.org/10.4155/fmc-2019-0241
  12. Novel radial distribution function approach in the study of point mutations: the HIV-1 protease case study vol.12, pp.11, 2003, https://doi.org/10.4155/fmc-2020-0042