Predicting structural effects in HIV-1 protease mutant complexes with flexible ligand docking and protein side-chain optimization.
We present a computational approach for predicting structures of ligand-protein complexes and analyzing binding energy landscapes that combines Monte Carlo simulated annealing technique to determine the ligand bound conformation with the dead-end elimination algorithm for side-chain optimization of the protein active site residues. Flexible ligand docking and optimization of mobile protein side-chains have been performed to predict structural effects in the V32I/I47V/V82I HIV-1 protease mutant bound with the SB203386 ligand and in the V82A HIV-1 protease mutant bound with the A77003 ligand. The computational structure predictions are consistent with the crystal structures of these ligand-protein complexes. The emerging relationships between ligand docking and side-chain optimization of the active site residues are rationalized based on the analysis of the ligand-protein binding energy landscape.
Agouron Pharmaceuticals, Inc., La Jolla, California 92037, USA.
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Schaffer
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Verkhivker
D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry; D015497:HIV-1 / Q000201:enzymology*; D007093:Imidazoles / Q000737:chemistry; D008024:Ligands; D009010:Monte Carlo Method; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation
C089787:2-phenylmethyl-4-hydroxy-5-(tert-butoxycarbonyl)amino-6-phenylhexanoyl-N-(1'-imidazol-2-yl)-2-'-methylpropanamide; D017320:HIV Protease Inhibitors; D007093:Imidazoles; D008024:Ligands; D016333:HIV Protease