Molecular modeling studies suggest that zinc ions inhibit HIV-1 protease by binding at catalytic aspartates.
Human immunodeficiency virus type 1 protease is inhibited in vitro by zinc ions at neutral pH. The binding site of these ions is not known; however, 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 have been carried out to 200 psec. The results are compared with the 2.8-A crystallographic structures 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 remains stably bound in this region, coordinating the carboxylate side chains of both aspartate residues. Interaction with zinc does not disrupt the dimeric structure of the protein or significantly alter the structure of the active site. These data are consistent with experimental studies of HIV-1 protease inhibition by zinc and give strong evidence that this is the binding site that leads to inactivation.
York
D M
DM
Laboratory of Molecular Toxicology, National Institute of Environment Health Sciences, Research Triangle Park, NC 27709.
Darden
T A
TA
Pedersen
L G
LG
Anderson
M W
MW
D001224:Aspartic Acid / Q000378:metabolism*; D001665:Binding Sites; D017320:HIV Protease Inhibitors / Q000378:metabolism*; D008954:Models, Biological; D008956:Models, Chemical; D015032:Zinc / Q000378:metabolism*
D017320:HIV Protease Inhibitors; D001224:Aspartic Acid; D015032:Zinc