Molecular dynamics study of the proposed beta-hairpin form of the switch domain from HIV1 gp120 alone and complexed with an inhibitor of CD4 binding

The strong tendency of beta-hairpin peptides to aggregate can prevent their structural resolution. The polar form of the switch peptide (LAV 15mer) at the CD4-binding domain of HIV1 gp120 is such a peptide, and NMR investigat ions of its interaction with a class of CD-l-binding inhibitors developed i n this laboratory have been hindered. Detailed knowledge of the interaction is required for the development of more potent switch inhibitors, that act by disrupting the cooperative folding transition necessary for binding to the CD4 receptor. In carrying out molecular dynamics simulation of the free peptide under polar conditions, we found that the properties of the result ing structure agree closely with those observed by circular dichroism. The same conditions, used to model the peptide/inhibitor complex, produced a st able bimolecular structure with specific interactions between the inhibitor and side chains on the peptide, (e.g., Trp(12) and the LPCR tetrad), known to control the folding transition. These help explain existing data on the relative potency of inhibitor derivatives and provide a basis for improved inhibitor design. (C) 1999 Wiley-Liss, Inc.