Ligand-guided receptor optimization.
Receptor models generated by homology or even obtained by crystallography often have their binding pockets suboptimal for ligand docking and virtual screening applications due to insufficient accuracy or induced fit bias. Knowledge of previously discovered receptor ligands provides key information that can be used for improving docking and screening performance of the receptor. Here, we present a comprehensive ligand-guided receptor optimization (LiBERO) algorithm that exploits ligand information for selecting the best performing protein models from an ensemble. The energetically feasible protein conformers are generated through normal mode analysis and Monte Carlo conformational sampling. The algorithm allows iteration of the conformer generation and selection steps until convergence of a specially developed fitness function which quantifies the conformer's ability to select known ligands from decoys in a small-scale virtual screening test. Because of the requirement for a large number of computationally intensive docking calculations, the automated algorithm has been implemented to use Linux clusters allowing easy parallel scaling. Here, we will discuss the setup of LiBERO calculations, selection of parameters, and a range of possible uses of the algorithm which has already proven itself in several practical applications to binding pocket optimization and prospective virtual ligand screening.