Predicting structural effects in HIV-1 protease mutant complexes with flexible ligand docking and protein side-chain optimization

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Abstract
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. Proteins 33:295–310, 1998.