Abstract
Evolutionary and structurally conserved fragments 24–34 and 83–93 from each of the HIV–1 protease (HIV–1 PR) monomers constitute the critical components of the HIV–1 PR folding nucleus. It has been recently discovered that the peptide with the amino acid sequence NIIGRNLLTQI identical to the corresponding segment 83–93 of the HIV–1 PR monomer, can inhibit folding of HIV–1 PR. We have previously shown that this peptide can form stable complexes with the folded HIV–1 PR monomer by targeting the conserved segment 24–34 of the folding nucleus (folding inhibition) and by interacting with the antiparallel termini β–sheet region (dimerization inhibition). In this follow-up study, we propose a generalized, coarse–grained model of the folding inhibition based simulations with an ensemble of both folded and partially unfolded HIV–1 PR conformational states. Using a dynamic equilibrium between low–energy complexes formed with the folded and partially unfolded HIV–1 PR monomers, the NIIGRNLLTQI peptide may effectively intervene with the HIV–1 PR folding and dimerization. The performed microscopic analysis reconciles the experimental and computational results and rationalizes the molecular basis of folding inhibition.
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References
Kohl, N.E., Emini, E.A., Schleif, W.A., Davis, L.J., Heimbach, J.C., Dixon, R.A., Scolnick, E.M., Sigal, I.S.: Active human immunodeficiency virus protease is required for viral infectivity. Proc. Natl. Acad. Sci. U. S. A. 85, 4686–4690 (1988)
Wlodawer, A., Vondrasek, J.: Inhibitors of HIV–1 protease: A major success of structure-assisted drug design. Annu. Rev. Biophys. Biomol. Struct. 27, 249–284 (1998)
Vondrasek, J., Wlodawer, A.: HIVdb: a database of the structures of human immunodeficiency virus protease. Proteins 49, 429–431 (2002)
Martin, P., Vickrey, J.F., Proteasa, G., Jimenez, Y.L., Wawrzak, Z., Winters, M.A., Merigan, T.C., Kovari, L.C.: “Wide-open” 1.3 A structure of a multidrug-resistant HIV–1 protease as a drug target. Structure 13, 1887–1895 (2005)
Ishima, R., Freedberg, D.I., Wang, Y.X., Loui, J.M., Torchia, D.A.: Flap opening and dimer-interface flexibility in the free and inhibitor bound HIV protease and their implications for function. Structure 7, 1047–1055 (1999)
Freedberg, D.I., Ishima, R., Jacob, J., Wang, Y.X., Kustanovich, I., Louis, J.M., Torchia, D.A.: Rapid structural fluctuations of the free HIV protease flaps in solution: relationship to crystal structures and comparison with predictions of dynamics calculations. Protein Sci. 11, 221–232 (2002)
Katoh, E., Louis, J.M., Yamazaki, T., Gronenborn, A.M., Torchia, D.A., Ishima, R.: A solution NMR study of the binding kinetics and the internal dynamics of an HIV–1 protease-substrate complex. Protein Sci. 12, 1376–1385 (2003)
Scott, W.R., Schiffer, C.A.: Curling of flap tips in HIV–1 protease as a mechanism for substrate entry and tolerance of drug resistance. Structure 8, 1259–1265 (2000)
Kurt, N., Scott, W.R., Schiffer, C.A., Haliloglu, T.: Cooperative fluctuations of unliganded and substrate-bound HIV–1 protease: a structure-based analysis on a variety of conformations from crystallography and molecular dynamics simulations. Proteins 51, 409–422 (2003)
Perryman, A.L., Lin, J.H., McCammon, J.A.: HIV–1 protease molecular dynamics of a wild-type and of the V82F/I84V mutant: possible contributions to drug resistance and a potential new target site for drugs. Protein Sci. 13, 1108–1123 (2004)
Perryman, A.L., Lin, J.H., McCammon, J.A.: Restrained molecular dynamics simulations of HIV–1 protease: the first step in validating a new target for drug design. Biopolymers 82, 272–284 (2007)
Hornak, V., Okur, A., Rizzo, R.C., Simmerling, C.: HIV–1 protease flaps spontaneously close to the correct structure in simulations following manual placement of an inhibitor into the open state. J. Am. Chem. Soc. 128, 2812–2813 (2006)
Hornak, V., Okur, A., Rizzo, R.C., Simmerling, C.: HIV–1 protease flaps spontaneously open and reclose in molecular dynamics simulations. Proc. Natl. Acad. Sci. U S A 103, 915–920 (2006)
Wallqvist, A., Smythers, G., Covell, G.: A cooperative folding unit in HIV–1 protease. Implications for protein stability and occurrence of drug-induced mutations. Protein Eng. 11, 999–1005 (1998)
Bhavesh, N.S., Sinha, R., Mohan, P.M., Hosur, R.V.: NMR elucidation of early folding hierarchy in HIV–1 protease. J. Biol. Chem. 278, 19980–19985 (2003)
Chatterjee, A., Hosur, R.V.: Following autolysis in proteases by NMR: insights into multiple unfolding pathways and mutational plasticities. Biophys. Chem. 123, 1–10 (2006)
Louis, J.M., Wondrak, E.M., Kimmel, A.R., Wingfield, P.T., Nashed, N.T.: Proteolytic processing of HIV–1 protease precursor, kinetics and mechanism. J. Biol. Chem. 274, 23437–23442 (1999)
Louis, J.M., Clore, G.M., Gronenborn, A.M.: Autoprocessing of HIV–1 protease is tightly coupled to protein folding. Nat. Struct. Biol. 6, 868–875 (1999)
Chatterjee, A., Mridula, P., Mishra, R.K., Mittal, R., Hosur: Folding regulates autoprocessing of HIV–1 protease precursor. J. Biol. Chem. 280, 11369–11378 (2005)
Ishima, R., Ghirlando, R., Tozser, J., Gronenborn, A.M., Torchia, D.A., Louis, J.M.: Folded monomer of HIV–1 protease. J. Biol. Chem. 276, 49110–49116 (2001)
Louis, J.M., Ishima, R., Nesheiwat, I., Pannell, L.K., Lynch, S.M., Torchia, D.A., Gronenborn, A.M.: Revisiting monomeric HIV–1 protease. Characterization and redesign for improved properties. J. Biol. Chem. 278, 6085–6092 (2003)
Ishima, R., Torchia, D.A., Lynch, S.M., Gronenborn, A.M., Louis, J.M.: Solution structure of the mature HIV–1 protease monomer: insight into the tertiary fold and stability of a precursor. J. Biol. Chem. 278, 43311–43319 (2003)
Ishima, R., Torchia, D.A., Louis, J.M.: Mutational and structural studies aimed at characterizing the monomer of HIV–1 protease and its precursor. J. Biol. Chem. 282, 17190–17199 (2007)
Bannwarth, L., Reboud-Ravaux, M.: An alternative strategy for inhibiting multidrug-resistant mutants of the dimeric HIV-1 protease by targeting the subunit interface. Biochem. Soc. Trans. 35, 551–554 (2007)
Broglia, R.A., Provasi, D., Vasile, F., Ottolina, G., Longhi, R., Tiana, G.: A folding inhibitor of the HIV-1 protease. Proteins 62, 928–933 (2005)
Broglia, R.A., Tiana, G., Sutto, L., Provasi, D., Simona, F.: Design of HIV-1-PR inhibitors that do not create resistance: blocking the folding of single monomers. Protein Sci. 14, 2668–2681 (2005)
Bonomi, M.F., Gervasio, L., Tiana, G., Provasi, D., Broglia, R.A., Parrinello, M.: Insight into the folding inhibition of the HIV-1 protease by a small peptide. Biophys. J. 93, 2813–2821 (2007)
Verkhivker, G., Tiana, G., Camilloni, C., Provasi, D., Broglia, R.A.: Atomistic simulations of the HIV-1 protease folding inhibition. Biophys. J. 95, 550–562 (2008)
Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., Bourne, P.E.: The Protein Data Bank. Nucleic Acids R. 28, 235–242 (2000)
Christen, M., Hunenberger, P.H., Bakowies, D., Baron, R., Burgi, R., Geerke, D.P., Heinz, T.N., Kastenholz, M.A., Krautler, V., Oostenbrink, C., Peter, C., Trzesniak, D., van Gunsteren, W.F.: The GROMOS software for biomolecular simulation: GROMOS 2005. J. Comput. Chem. 26, 1719–1751 (2005)
Verkhivker, G.M.: Computational proteomics of biomolecular interactions in the sequence and structure space of the tyrosine kinome: deciphering the molecular basis of the kinase inhibitors selectivity. Proteins 66, 912–929 (2007)
Verkhivker, G.M.: In silico profiling of tyrosine kinases binding specificity and drug resistance using Monte Carlo simulations with the ensembles of protein kinase crystal structures. Biopolymers 85, 333–348 (2007)
Cornell, W.D., Cieplak, P., Bayly, C.L., Gould, I.R., Merz, K.M., Ferguson, D.M., Spellmeyer, D.C., Fox, T., Caldwell, J.W., Kollman, P.A.: A second generation force field for simulation of proteins, nucleic acids, and organic molecules. J. Amer. Chem. Soc. 117, 5179–5197 (1995)
Stouten, P.F.W., Frömmel, C., Nakamura, H., Sander, C.: An effective solvation term based on atomic occupancies for use in protein simulations. Mol. Simul. 10, 97–120 (1993)
Sugita, Y., Okamoto, Y.: Replica-exchange molecular dynamics method for protein folding. Chem. Phys. Lett. 314, 141–151 (1999)
Shoemaker, B.A., Portman, J.J., Wolynes, P.G.: Speeding molecular recognition by using the folding funnel: the fly-casting mechanism. Proc. Natl. Acad. Sci. U S A 97, 8868–8873 (2000)
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Verkhivker, G.M. (2009). Coarse-Grained Modeling of the HIV–1 Protease Binding Mechanisms: II. Folding Inhibition. In: Masulli, F., Tagliaferri, R., Verkhivker, G.M. (eds) Computational Intelligence Methods for Bioinformatics and Biostatistics. CIBB 2008. Lecture Notes in Computer Science(), vol 5488. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-02504-4_2
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DOI: https://doi.org/10.1007/978-3-642-02504-4_2
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