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

Abstract

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 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 twenty 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.

Native or Non-Native Protein–Protein Docking Models? Molecular Dynamics to the Rescue

“… 15 − 21 MD can be used at a more extensive level, where the docking process is simulated; however, modeling spontaneous association and dissociation of proteins is very rare unless coarse-grained models or enhanced sampling methods are used. 22 − 25 With regard to all-atom MD simulations, enhanced sampling techniques like Markov states models, 26 − 29 umbrella sampling combined with replica exchange MD, 30 − 35 elastic-network approaches, 35 string method, 36 metadynamics, 37 , 38 and other methods have been used to sample conformational change prior to or during binding and to facilitate such binding events under the condition that the binding interface is known. 39 Such simulations also present a great opportunity to evaluate binding affinities of known protein–protein complexes.…”

“…Another persisting challenge, which is to different extents addressed by protein–protein docking programs, is protein flexibility. − Molecular dynamics (MD) can account for conformational changes needed for binding at different levels. On a smaller scale, i.e., at the level of atoms, sidechains, loops, small molecules, or interfaces, MD is commonly applied to refine docked complexes with the aim of improving their quality. − MD can be used at a more extensive level, where the docking process is simulated; however, modeling spontaneous association and dissociation of proteins is very rare unless coarse-grained models or enhanced sampling methods are used. − With regard to all-atom MD simulations, enhanced sampling techniques like Markov states models, − umbrella sampling combined with replica exchange MD, − elastic-network approaches, string method, metadynamics, , and other methods have been used to sample conformational change prior to or during binding and to facilitate such binding events under the condition that the binding interface is known . Such simulations also present a great opportunity to evaluate binding affinities of known protein–protein complexes.…”

Molecular Insights Into Binding and Activation of the Human KCNQ2 Channel by Retigabine

“…Volume and druggability calculations. Druggability calculations were performed using the f-pocket ( Le Guilloux et al, 2009 ) software as described in previous publications ( Basciu et al, 2019b ; Basciu et al, 2019a ). For each conformation of the protein extracted from the cluster analysis described above, we evaluated its druggability score D, a descriptor ranging from 0 to 1 with higher values identifying more druggable geometries ( Schmidtke and Barril, 2010 ).…”

Native or non-native protein-protein docking models? Molecular dynamics to the rescue

“…(15)(16)(17)(18)(19)(20)(21) MD can be used at a more extensive level, where the docking process is simulated, however modelling spontaneous association and dissociation of proteins is very rare unless coarse-grained models or enhanced sampling methods are used. (22)(23)(24)(25) With regard to all-atom MD simulations, enhanced sampling techniques like Markov states models, (26)(27)(28)(29) umbrella sampling combined with replica exchange MD, (30)(31)(32)(33)(34)(35) elastic-network approaches (35), string method (36), metadynamics (37,38) and other methods have been used to sample conformational change prior to or during binding and to facilitate such binding events under the condition that the binding interface is known (39). Such simulations also present a great opportunity to evaluate binding affinities of known protein-protein complexes.…”