Methodology for protein-ligand binding studies: Application to a model fordrug resistance, the HIV/FIV protease system

A protocol for the rapid energetic analysis of protein-ligand complexes has been developed. This protocol involves the generation of protein-ligand co mplex ensembles followed by an analysis of the binding free energy componen ts. We apply this methodology toward understanding the origin of binding sp ecificity within the human immunodeficiency virus/feline immunodeficiency v irus (HIV/FIV) protease system, a model system for drug resistance studies. A distinct difference in the internal strain of an inhibitor within each p rotein environment clearly favors the HIV protease complex, as observed exp erimentally. Our analysis also predicts that residues within the S2-S3 pock ets of the FIV protease active site are responsible for this strain. Close examination of the active site residue contributions to interaction energy and desolvation energy identifies specific amino acids that may also play a role in determining the binding preferences of these two enzymes. (C) 1999 Wiley-Liss, Inc.