coREF: A COMBINED REFINEMENT APPROACH FOR GPCRs BACKBONE FLEXIBILITY

Abstract

Two challenges for G-protein coupled receptor (GPCR)-ligand docking with flexibility by computational method are: (1) how to accurately model the perturbations of the backbone when docking ligand to the receptor and (2) how to sample the backbone near the binding pocket. To address the two challenges, we propose a combined refinement (coREF) approach working on the flexibility of the docking interface by integrating two different refinement protocols based on RosettaLigand (RL) platform. The first refinement protocol generates multiple initial receptors by parallelling different movements to mimic the observed simultaneous fluctuations of backbones near the binding site without ligand conformation. The second refinement protocol adds a backbone refinement step for interface residues with ligand conformation, which extending the RL docking algorithm. To validate the performance of coREF, we refined 20 GPCR Docking 2008/2010 models submitted by participants. Eight of 10 CXCR4 targets and half of D3 targets showed lower LRMSD values than the submitted models. Nine in 12 results were slightly better than those refined using the RL docking algorithm.