Studies on the specificity of HIV protease: an application of Markov chain theory.
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.
Chou
K C
KC
Upjohn Laboratories, Kalamazoo, Michigan 49001-4940.
Zhang
C T
CT
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D015195:Drug Design; D016333:HIV Protease / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology; D015498:HIV-2 / Q000201:enzymology; D006801:Humans; D008390:Markov Chains; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D010446:Peptide Fragments / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D013379:Substrate Specificity
D000998:Antiviral Agents; D010446:Peptide Fragments; D011506:Proteins; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease; C065184:p16 protease, Human immunodeficiency virus 2