Protein Docking Refinement with Systematic Conformational Search - Application to Models Inside the Docking Funnel

Abstract

Structural refinement of modeled protein-protein complexes is an essential step in protein docking. Such refinement becomes increasingly challenging when the interacting proteins undergo significant conformational changes upon binding (unbound/bound interface RMSD>3 Å). We developed a flexible interface refinement protocol and benchmarked it on a set of top 100 docking models, which are inside the docking funnel (C-alpha ligand interface RMSD ≤ 10 Å [1]), generated for binary protein-protein complexes from the Dockground X-ray unbound set 4.0 (http://dockground.compbio.ku.edu). The refinement of the docking models was performed by a systematic local conformational search using previously developed Atom-Atom Contact Energy (AACE18) [2]. The average numbers of models of acceptable or better quality (according to CAPRI criteria [3]) in top-10 refined structures were 4.2, 3.0, and 1.7, for easy (unbound/bound interface RMSD ≤ 1.5 Å), medium (1.5 - 2.2 Å) and difficult (> 2.2 Å) docking targets, respectively. The results showed that the procedure performs better than other widely used refined protocols benchmarked on the same set of protein-protein complexes. 1. Hunjan et al. Proteins, 2008, 72: 344-352. 2. Anishchenko et al. Biophys. J., 2018, 115: 809-821. 3. Mendez et al. Proteins, 2003, 52: 51-67.