Abstract
A sequence-coupled (Markov chain) model is proposed to predict the cleavage sites in proteins by proteases with extended specificity subsites. In addition to the probability of an amino acid occurring at each of these subsites as observed from a training set of oligopeptides known cleavable by HIV protease, the conditional probabilities as reflected by the neighbor-coupled effect along the subsite sequence are also taken into account. These conditional probabilities are derived from an expanded training set consisting of sufficiently large peptide sequences generated by the Monte Carlo sampling process. Very high accuracy was obtained in predicting protein cleavage sites by both HIV-1 and HIV-2 proteases. The new method provides a rapid and accurate means for analyzing the specificity of HIV protease, and hence can be used to help find effective inhibitors of HIV protease as potential drugs against AIDS. The principle of this method can also be used to study the specificity of any multisubsite enzyme.
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Barré-Sinoussi, F., Chermann, J. C., Rey, F., Nugeyre, M. T., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vézinet-Brun, F., Rouzioux, C., Rozenbaum, W., and Montagnier, L. (1983).Science 220 868–871.
Bhat, U. N. (1984).Elements of Applied Stochastic Processes, Chap. 3, John Wiley & Sons, New York.
Chou, K. C. (1993).J. Biol. Chem. 268 16938–16948.
Chou, K. C., and Zhang, C. T. (1992)Eur. J. Biochem. 207 429–433.
Chou, K. C., and Zhang, C. T. (1992).AIDS Research Human Retroviruses 8 1967–1976.
Chou, K. C., Chen, N. Y., and Forsén, S. (1981).Chemica Scripta 18 126–132.
Efron, B. (1990). “The Jacknife, the Bootstrap and Other Resampling Plans,” Chap. 5, Society for Industrial and Applied Mathematics, Philadelphia, Pennsylvania.
Gallo, R. C., Salahuddin, S. Z., Popovic, M., Shearer, G. M. Kaplan, M., Haynes, B. F., Palker, T. J., Redfield, R., Oleske, J., Safai, B., White, G., Foster, P., and Markham, P. D. (1984).Science 224 500–503.
Griffiths, J. T., Phylip, L. H., Konvalinka, J., Strop, P., Gustchina, A., Wlpdawer, A., Davenport, R., Briggs, R., Dunn, B. M., and Kay, J. (1992).Biochemistry 31 5193–5200.
Goodenow, M., Huet, T., Saurin, W., Kwok, S., Sninsky, J., and Wain-Hobson, S. (1989).J. Acquir. Immune. Defic. Syndr. 2 344–352.
Harte, W. E. Jr., Swaminathan, S., and Beveridge, D. (1992).Proteins Struct. Funct. Genet. 13 175–194.
Hellen, C. U. T., Kräusslich, H. G., and Wimmer, E. (1989).Biochemistry 28 9881–9890.
Henderson, L. E., Benveniste, R. E., Sowder, R. C., Copeland, T. D., Schutz, A. M., and Oroszlan, S. (1988).J. Virol. 62 2587–2595.
Kabsch, W., and Sander, C. (1983).FEBS Letters 155 179–182.
Kohl, N. E., Emini, E. A., Schlief, W. A., Davis, L. J., Heimbach, J., Dixon, R. A. F., Scolnik, E. M., and Sigal, I. S. (1988).Proc. Natl. Sci. USA 85 4686–4690.
Kypr, J., and Mrázek, J. (1987).Nature 327 20.
Lapatto, R., Blundell, T., Hemmings, A., Overington, J., Wilderspin, A., Wood, S., Merson, J. R., White, P. J., Danley, D. E., Geoghegan, K. F., Hawrylik, S. J., Lee, S. W., Scheld, K. G., and Hobart, P. M. (1989).Nature 342 299–302.
Martel, P. (1992).Prog. Biophys. Molec. Biol. 57 129–179.
Miller, M., Schneider, J., Sathyanarayana, B. K., Toth, M. V., Marshall, G. R., Clawson, L., Selk, L., Kent, S. B. H., and Wlodawer, A. (1989).Science 246 1149–1152.
Navia, M. A., Fitzgerald, P. M. D., McKeever, B. M., Leu, C. T., Heimbach, J. C., Herber, W. K., Sigal, I. S., Darke, P. L., and Springer, J. P. (1989).Nature 337 615–620.
Partin, K., Kräusslich, H. G., Ehrlich, L., Wimmer, E., and Carter, C. (1990).J. Virol. 64 3938–3947.
Pearl, L., and Taylor, W. (1987).Nature 329 351–354.
Poorman, R. A., Tomasselli, A. G., Heinrikson, R. L., and Kézdy, F. J. (1991).J. Biol. Chem. 266 14,554–14,561.
Putney, S. (1992).TIBS 17 191–196.
Rowe, G. W., Szabo, V. L., and Trainor, L. E. (1984).J. Mol. Evol. 20 167–174.
Schechter, I., and Berger, A. (1967).Biochem. Biophys. Res. Com. 27 157–162.
Sharp, P. M. (1986).Nature 324 114–114.
Toh, H., Ono, M., Saigo, K., and Miyata, T. (1985).Nature 315 691.
Tözsér, J., Weber, I. T., Gustchina, A., Bláha, I., Copeland, T. D., Louis, J. M., and Oroszlan, S. (1992).Biochemistry 31 4793–4800.
Vartanian, J. P., Meyerhans, A., Asjo, B., and Wain-Hobson, S. (1991).J. Virol. 65 1779–1788.
Wain-Hobson, S. (1989).AIDS 3 13–18.
Wlodawer, A., Miller, M., Jaskólski, M., Sathyanarayana, B. K., Baldwin, E., Weber, I. T., Selk, L. M., Clawson, L., Schneider, J., and Kent, S. B. H. (1989).Science 245 616–621.
Zhang, C. T., and Chou, K. C. (1992).Biophysical Journal 63 1523–1529.
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Chou, KC., Zhang, CT. Studies on the specificity of HIV protease: An application of Markov chain theory. J Protein Chem 12, 709–724 (1993). https://doi.org/10.1007/BF01024929
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DOI: https://doi.org/10.1007/BF01024929