Molecular dynamics simulations of a complex of HIV-1 protease and substrate: substrate-dependent efficiency of catalytic activity

We carried out molecular dynamics (MD) simulations of the HIV-1 protease (HIV-1 PR)-substrate complex and examined the efficiency of the catalytic activity in terms of the difference in the structures of the substrates. Four kinds of substrates were used in this work: three substrate peptides composed of the sequence of the natural cleavage site by HIV-I PR (Ac-Gln-Asn-Tyr-Pro-Ile-Val-NMe, Ac-Ser-Gln-Asn-Tyr-Pro-Ile-Val-NMe, and Ac-Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Nme) and another substrate peptide in which Leu is substituted at the P4 position (Ac-Val-Leu-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Nme). simulations revealed that the first three kinds of the HPV-I PR-substrate complexes maintain a specific conformation for initiating catalytic reaction, but the last HIV-I PR-substrate complex does not. Our results suggest that the first three substrate peptides are hydrolyzed when the respective ES complexes were formed. In contrast, a catalytic reaction seldom occurs for the last substrate peptide, even if it combined with HIV-I PR. (C) 2001 Elsevier Science B.V. All rights reserved.