Expanding GPCR homology model binding sites via a balloon potential: A molecular dynamics refinement approach

Homology modeling of G protein-coupled receptors is becoming a widely used tool in drug discovery. However, unrefined models built using the bovine rhodopsin crystal structure as the template, often have binding sites that are too small to accommodate known ligands. Here, we present a novel systematic method to refine model active sites based on a pressure-guided molecular dynamics simulation. A distinct advantage of this approach is the ability to introduce systematic perturbations in model backbone atoms in addition to side chain adjustments. The method is validated on two test cases: (1) docking of retinal into an MD-relaxed structure of opsin and (2) docking of known ligands into a homology model of the CCR2 receptor. In both cases, we show that the MD expansion algorithm makes it possible to dock the ligands in poses that agree with the crystal structure or mutagenesis data.