GeauxDock: A novel approach for mixed‐resolution ligand docking using a descriptor‐based force field

Abstract

Molecular docking is an important component of computer-aided drug discovery. In this communication, we describe GeauxDock, a new docking approach that builds on the ideas of ligand homology modeling. GeauxDock features a descriptor-based scoring function integrating evolutionary constraints with physics-based energy terms, a mixed-resolution molecular representation of protein-ligand complexes, and an efficient Monte Carlo sampling protocol. To drive docking simulations toward experimental conformations, the scoring function was carefully optimized to produce a correlation between the total pseudoenergy and the native-likeness of binding poses. Indeed, benchmarking calculations demonstrate that GeauxDock has a strong capacity to identify near-native conformations across docking trajectories with the area under receiver operating characteristics of 0.85. By excluding closely related templates, we show that GeauxDock maintains its accuracy at lower levels of homology through the increased contribution from physics-based energy terms compensating for weak evolutionary constraints. GeauxDock is available at http://www.institute.loni.org/lasigma/package/dock/.

Assessing the similarity of ligand binding conformations with the Contact Mode Score

“…After each round of perturbation, RMSD and CMS were computed against the native conformation of a ligand. The second simulated dataset contains Metropolis Monte Carlo (MMC) trajectories constructed by GeauxDock (Ding et al, 2015) for Astex/CCDC complexes. GeauxDock employs a mixed-resolution representation of protein-ligand complexes and a hybrid scoring function comprising physics-, evolution-based energy terms and statistical potentials.…”

“…GeauxDock effectively finds the near native structures of protein-ligand complexes by exploring low-energy configurations according to a dimensionless scoring function. Here, binding ligands were initialized at random conformations and GeauxDock simulation engine (Ding et al, 2015) was used to generate docking trajectories through 800 MMC cycles. The CMS was calculated for each accepted conformation against the ligand bound in the crystal complex structure.…”

“…Small side chains of Ala, Asn, Asp, Cys, Ile, Leu, Pro, Ser, Thr and Val are reduced to one pseudo atom located at the geometric center, whereas longer side chains of Arg, Gln, Glu, His, Lys, Met, Phe, Trp and Tyr are described by twoeffective points corresponding to the middle of a virtual Cβ-Cγ bond and the geometric center of the remaining side-chain atoms (Zacharias, 2003). It is noteworthy that this model is already implemented in a molecular docking program, GeauxDock (Ding et al, 2015). In XCMS, two effective points per residue are used at the positions of its Cα and Cβ atoms ( CA and CB , respectively), except for glycine that has only the CA atom.…”

“…On the other hand, the development and optimization of scoring functions for molecular docking often involves tuning force field parameters against diverse datasets of protein-ligand complexes. For example, weight factors can be adjusted to maximize the capability to recognize near native conformations amongst a large set of docking decoys (Brylinski and Skolnick, 2009a, 2008; Ding et al, 2015). An imprecise classification of near native and decoy conformations, e.g.…”

Reliability analysis and optimization of the consensus docking approach for the development of virtual screening studies

“…Docking is also largely used for hit identification, representing the main example of receptor-based virtual screening (VS) procedure: a docking-based approach is commonly reported in several successful VS studies, both alone and in combination with other computational strategies [4][5][6][7][8] . For these reasons, the exponential attention that docking is gaining over time, as proved by the number of novel docking procedures and scoring functions reported in literature only in the last few years, cannot be blamed [9][10][11][12][13][14][15][16][17][18][19][20] . However, the remarkable interest for docking and for the development of new and optimized approaches is mainly due to the fact that the prediction of the actual binding mode of a ligand into a protein target is still far from being an easy task.…”