Biopolym. Cell. 2002; 18(2):117-123.
http://dx.doi.org/10.7124/bc.0005F2
Конформаційні зміни в структурі ВІЛ-1 протеази: дослідження методом молекулярної динаміки в піко- та наносекундному часових проміжках
1Ковальський Д. Б., 1Корнелюк О. І.
  1. Інститут молекулярної біології і генетики НАН України
    Вул. Академіка Заболотного, 150, Київ, Україна, 03680

Abstract

ВІЛ-1 протеаза є однією з найпривабливіших моделей для дизайну лікарських засобів у терапії СНІДу. Для потрапляння субстрату до активного центра протеази необхідно, щоб дві β-шпильки («флепи»), які його покривають, відкрилися на достатню для цього відстань. Саме тому «флепи» відіграють ключову роль у функціонуванні ВІЛ-1 протеази. Незважаючи нгрунтовні знання структури цього ферменту, до теперіш­нього часу немає даних стосовно механізму відкриття «флепів». Саме тому здійснено симуляцію молекулярної динаміки ВІЛ-1 протеази у вакуумі та водному розчині в піко- та наносекундному часових проміжках. Спостерігалося фомування структурного «динамічного» сайта зв'язування як у нс-так і в пс-часових проміжках. «Динамічний» карман утво­рюється, в основному, з гідрофобних амінокислотних залишків, а саме: Val32, Lys45, Ile47, Gly48, Gly49fб Ile50, Gly51, Gly52, Ile54, Val56, Leu76, Gly78, Pro79, Thr80, Pro81. Він залишається добре визначеним впродовж усього періоду симуляїі Пропонується використання цього карману для дизайну лікарських засобів
Повний текст: (PDF, російською)

References

[1] Robins T, Plattner J. HIV protease inhibitors: their anti-HIV activity and potential role in treatment. J Acquir Immune Defic Syndr. 1993;6(2):162-70.
[2] Navia MA, Fitzgerald PM, McKeever BM, Leu CT, Heimbach JC, Herber WK, Sigal IS, Darke PL, Springer JP. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature. 1989;337(6208):615-20.
[3] Wlodawer A, Miller M, Jask?lski M, Sathyanarayana BK, Baldwin E, Weber IT, Selk LM, Clawson L, Schneider J, Kent SB. Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science. 1989;245(4918):616-21.
[4] Lapatto R, Blundell T, Hemmings A, Overington J, Wilderspin A, Wood S, Merson JR, Whittle PJ, Danley DE, Geoghegan KF, et al. X-ray analysis of HIV-1 proteinase at 2.7 A resolution confirms structural homology among retroviral enzymes. Nature. 1989;342(6247):299-302.
[5] Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RA, Scolnick EM, Sigal IS. Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci U S A. 1988;85(13):4686-90.
[6] Peng C, Ho BK, Chang TW, Chang NT. Role of human immunodeficiency virus type 1-specific protease in core protein maturation and viral infectivity. J Virol. 1989;63(6):2550-6.
[7] Wlodawer A, Erickson JW. Structure-based inhibitors of HIV-1 protease. Annu Rev Biochem. 1993;62:543-85.
[8] De Lucca GV, Erickson-Viitanen S, Lam PYS. Cyclic HIV protease inhibitors capable of displacing the active site structural water molecule. Drug Discov Today. 1997;2(1):6–18.
[9] Roberts NA, Martin JA, Kinchington D, Broadhurst AV, Craig JC, Duncan IB, Galpin SA, Handa BK, Kay J, Kr?hn A, et al. Rational design of peptide-based HIV proteinase inhibitors. Science. 1990;248(4953):358-61.
[10] Craig JC, Duncan IB, Hockley D, Grief C, Roberts NA, Mills JS. Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. Antiviral Res. 1991;16(4):295-305.
[11] Krohn A, Redshaw S, Ritchie JC, Graves BJ, Hatada MH. Novel binding mode of highly potent HIV-proteinase inhibitors incorporating the (R)-hydroxyethylamine isostere. J Med Chem. 1991;34(11):3340-2.
[12] Dorsey BD, Levin RB, McDaniel SL, Vacca JP, Guare JP, Darke PL, Zugay JA, Emini EA, Schleif WA, Quintero JC, et al. L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem. 1994;37(21):3443-51.
[13] Chen Z, Li Y, Chen E, Hall DL, Darke PL, Culberson C, Shafer JA, Kuo LC. Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases. J Biol Chem. 1994;269(42):26344-8.
[14] Kempf DJ, Marsh KC, Denissen JF, McDonald E, Vasavanonda S, Flentge CA, Green BE, Fino L, Park CH, Kong XP, et al. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc Natl Acad Sci U S A. 1995;92(7):2484-8.
[15] Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, Kati W, Stewart K, Lal R, Hsu A, Betebenner D, Korneyeva M, Vasavanonda S, McDonald E, Saldivar A, Wideburg N, Chen X, Niu P, Park C, Jayanti V, Grabowski B, Granneman GR, Sun E, Japour AJ, Leonard JM, Plattner JJ, Norbeck DW. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother. 1998;42(12):3218-24.
[16] Navia MA, Sato VL, Tung RD. Design of VX-478, a potent inhibitor of HIV protease. Int. Antiviral News. 1995; 3(9):143-5.
[17] Kim EE, Baker CT, Dwyer MD, Murcko MA, Rao BG, Tung RD, et al. Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme. J Am Chem Soc. 1995;117(3):1181–2.
[18] Kaldor SW, Kalish VJ, Davies JF 2nd, Shetty BV, Fritz JE, Appelt K, Burgess JA, Campanale KM, Chirgadze NY, Clawson DK, Dressman BA, Hatch SD, Khalil DA, Kosa MB, Lubbehusen PP, Muesing MA, Patick AK, Reich SH, Su KS, Tatlock JH. Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease. J Med Chem. 1997;40(24):3979-85.
[19] Kalish V, Kaldor S, Shetty B, Tatlock J, Davies J, Hammond M, Dressman B, Fritz J, Appelt K, Reich S, Musick L, Wu B, Su K. Iterative protein structure-based drug design and synthesis of HIV protease inhibitors. Eur J Med Chem. 1995; 30:201-14.
[20] Condra JH. Resistance to HIV protease inhibitors. Haemophilia. 1998;4(4):610-5. Review.
[21] Ridky T, Leis J. Development of drug resistance to HIV-1 protease inhibitors. J Biol Chem. 1995;270(50):29621-3.
[22] Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature. 1995;374(6522):569-71.
[23] Lange-Savage G, Berchtold H, Liesum A, Budt KH, Peyman A, Knolle J, Sedlacek J, Fabry M, Hilgenfeld R. Structure of HOE/BAY 793 complexed to human immunodeficiency virus (HIV-1) protease in two different crystal forms--structure/function relationship and influence of crystal packing. Eur J Biochem. 1997;248(2):313-22.
[24] Furfine ES, D'Souza E, Ingold KJ, Leban JJ, Spector T, Porter DJ. Two-step binding mechanism for HIV protease inhibitors. Biochemistry. 1992;31(34):7886-91.
[25] Ishima R, Wingfield PT, Stahl SJ, Kaufman JD, Torchia DA. Using Amide 1 H and 15 N Transverse Relaxation To Detect Millisecond Time-Scale Motions in Perdeuterated Proteins: Application to HIV-1 Protease. J Am Chem Soc. 1998;120(40):10534–42.
[26] Ishima R, Freedberg DI, Wang YX, Louis JM, Torchia DA. Flap opening and dimer-interface flexibility in the free and inhibitor-bound HIV protease, and their implications for function. Structure. 1999;7(9):1047-55.
[27] Froimowitz M. HyperChem: a software package for computational chemistry and molecular modeling. Biotechniques. 1993;14(6):1010-3.
[28] Jorgensen WL, Tirado-Rives J. The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. J Am Chem Soc. 1988;110(6):1657–66.
[29] Spinelli S, Liu QZ, Alzari PM, Hirel PH, Poljak RJ. The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie. 1991;73(11):1391-6.
[30] Bernstein FC, Koetzle TF, Williams GJ, Meyer EF Jr, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol. 1977;112(3):535-42.
[31] Van Gunsteren WF, Berendsen HJC. Algorithms for macromolecular dynamics and constraint dynamics. Mol Phys. 1977;34(5):1311-27.
[32] Lindahl E, Hess B, van der Spoel D. GROMACS 3.0: a package for molecular simulation and trajectory analysis. J Mol Model. 2001; 7: 306-31.
[33] Berendsen HJC, van der Spoel D, van Drunen R. GROMACS: A message-passing parallel molecular dynamics implementation. Comput Phys Commun. 1995;91(1-3):43–56.
[34] Ryckaert J-P, Ciccotti G, Berendsen HJ. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys. 1977;23(3):327–41.
[35] Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR. Molecular dynamics with coupling to an external bath. J Chem Phys. 1984;81(8):3684-90.
[36] Tironi IG, Sperb R, Smith PE, van Gunsteren WF. A generalized reaction field method for molecular dynamics simulations. J Chem Phys. 1995;102(13):5451-9.
[37] Rose RB, Craik CS, Stroud RM. Domain flexibility in retroviral proteases: structural implications for drug resistant mutations. Biochemistry. 1998;37(8):2607-21.
[38] York DM, Darden TA, Pedersen LG, Anderson MW. Molecular dynamics simulation of HIV-1 protease in a crystalline environment and in solution. Biochemistry. 1993;32(6):1443-53.
[39] Collins JR, Burt SK, Erickson JW. Activated dynamics of flap opening in HIV-1 protease. Adv Exp Med Biol. 1995;362:455-60.
[40] Rick SW, Erickson JW, Burt SK. Reaction path and free energy calculations of the transition between alternate conformations of HIV-1 protease. Proteins. 1998;32(1):7-16.
[41] Ishima R, Louis JM, Torchia DA. Characterization of two hydrophobic methyl clusters in HIV-1 protease by NMR spin relaxation in solution. J Mol Biol. 2001;305(3):515-21.
[42] Shao W, Everitt L, Manchester M, Loeb DD, Hutchison CA 3rd, Swanstrom R. Sequence requirements of the HIV-1 protease flap region determined by saturation mutagenesis and kinetic analysis of flap mutants. Proc Natl Acad Sci U S A. 1997;94(6):2243-8.