Flexible Cdocker: Development and Application of a Pseudo-Explicit Structure-Based Docking Method within Charmm

Abstract

Structure-based docking has become a commonly used method for ligand discovery and refinement, especially with the increased availability of high-resolution structural data. Traditionally, these methods represent protein targets as rigid receptors but proteins are fluid molecules that exist in an inter-converting ensemble of conformational states. Recently, docking protocols have trended towards incorporating protein flexibility but effectively and efficiently searching the conformational space available to proteins remains a well-appreciated computational challenge. To this end, we have developed a method utilizing CHARMM to incorporate side chain flexibility within grid-based docking methods, maintaining efficiency while allowing the protein and ligand conformations to be sampled simultaneously. This is unlike induced-fit docking methods that search only one conformational space, either protein or ligand, at a time. Presented here are results for re-docking and cross-docking simulations and an assessment of the benefits of incorporating flexibility in docking when compared to traditional rigid methods.