Coupling enhanced sampling of the apo-receptor with template-based ligand conformers selection: performance in pose prediction in the D3R Grand Challenge 4.

We report the performance of our newly introduced Ensemble Docking with Enhanced sampling of pocket Shape (EDES) protocol coupled to a template-based algorithm to generate near-native ligand conformations in the 2019 iteration of the Grand Challenge (GC4) organized by the D3R consortium. Using either AutoDock4.2 or HADDOCK2.2 docking programs (each software in two variants of the protocol) our method generated native-like poses among the top 5 submitted for evaluation for most of the 20 targets with similar performances. The protein selected for GC4 was the human beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), a transmembrane aspartic-acid protease. We identified at least one pose whose heavy-atoms RMSD was less than 2.5 Å from the native conformation for 16 (80%) and 17 (85%) of the 20 targets using AutoDock and HADDOCK, respectively. Dissecting the possible sources of errors revealed that: (i) our EDES protocol (with minor modifications) was able to sample sub-ångstrom conformations for all 20 protein targets, reproducing the correct conformation of the binding site within ~ 1 Å RMSD; (ii) as already shown by some of us in GC3, even in the presence of near-native protein structures, a proper selection of ligand conformers is crucial for the success of ensemble-docking calculations. Importantly, our approach performed best among the protocols exploiting only structural information of the apo protein to generate conformations of the receptor for ensemble-docking calculations.