MOLECULAR MODELING STUDIES SUGGEST THAT ZINC IONS INHIBIT HIV-1 PROTEASE BY BINDING AT CATALYTIC ASPARTATES

Human immunodeficiency vims type 1 protease is inhibited in vitro by z inc ions at neutral pH. The binding site of these ions is not known; h owever, experimental data suggest that binding may occur in the active site. To examine the possibility of zinc binding in the active site, molecular dynamics simulations in the presence and absence of zinc hav e been carried out to 200 psec. The results are compared with the 2.8- A crystallographic structure of a synthetic HIV-1 protease, and a zinc binding site at the catalytic aspartate residues (Asp-25, Asp-25') is proposed. Molecular dynamics simulations show that the zinc ion remai ns stably bound in this region, coordinating the carboxylate side chai ns of both aspartate residues. Interaction with zinc does not disrupt the dimeric structure of the protein or significantly alter the struct ure of the active site. These data are consistent with experimental st udies of HIV-1 protease inhibition by zinc and give strong evidence th at this is the binding site that leads to inactivation.