Applying Pose Clustering and MD Simulations To Eliminate False Positives in Molecular Docking

Abstract

In this work, we developed a computational protocol that employs multiple molecular docking experiments, followed by pose clustering, molecular dynamic simulations (10 ns), and energy rescoring to produce reliable 3D models of antibody–carbohydrate complexes. The protocol was applied to 10 antibody–carbohydrate co-complexes and three unliganded (apo) antibodies. Pose clustering significantly reduced the number of potential poses. For each system, 15 or fewer clusters out of 100 initial poses were generated and chosen for further analysis. Molecular dynamics (MD) simulations allowed the docked poses to either converge or disperse, and rescoring increased the likelihood that the best-ranked pose was an acceptable pose. This approach is amenable to automation and can be a valuable aid in determining the structure of antibody–carbohydrate complexes provided there is no major side chain rearrangement or backbone conformational change in the H3 loop of the CDR regions. Further, the basic protocol of docking a small ligand to a known binding site, clustering the results, and performing MD with a suitable force field is applicable to any protein ligand system.

Heterocycles 48. Synthesis, Characterization and Biological Evaluation of Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives as Anti-Inflammatory Agents

“…The clustering analysis is reported in the literature as a method of removal of the false positive results for the molecular docking study [ 32 , 33 ]. A compound with a high homogeneity in binding to the protein can be considered as a true binder.…”

“…Thus, a compound with a high homogeneity has a high number of conformations in the cluster of the best binding pose and a low number of other wandering conformations in other clusters, including few other conformations. Approaching the idea in the opposite direction, a compound with many clusters resulted after the molecular docking and with few poses in the same cluster can be considered as a false binder, having a high dispersion between conformations given by the different docking runs with random beginning positions [ 32 , 33 ]. The clustering analysis of the resulted bounds characteristic for the compounds 5a – l are presented in Table 5 .…”

Three-Dimensional Structures of Carbohydrates and Where to Find Them

“…Docking methods for carbohydrate ligands utilize molecular modeling approaches for protein-carbohydrate complexes for initial geometry generation, conformational sampling, grafting, active site mapping and binding affinity estimation [ 129 , 137 , 209 , 210 , 211 ]. Accurate reproduction of experimental data requires application of particular scoring function parameterization (empirical, force fields or knowledge-based [ 212 ]) and docking protocols, which depend on the interaction types present in a system (CH-π interactions, CHI-energy, hydrogen bonding, solvent model, influence of solvent molecules inclusion effects, charged moiety etc.)…”

Antibodies to the Cryptococcus neoformans Capsule have Innate Glycosidase Activity

“…In contrast a crystal structure of the fragment antigen-binding (Fab) domain of mAb 2H1 bound to a peptide mimetic of GXM was solved by Young and co-workers ( Figure 3B). 31 Using the PDB file and the open access modelling server GLYCAM, [32][33][34] we performed antibody docking studies to determine the glycan-antibody interactions for 2H1 ( Figure 3A, 3D). We performed docking studies with both acetylated (Supplementary Figure 6) and deacetylated ( Figure 3) GXM structures, with the highest scoring binding affinities predicted to be -10 kcal/mol for both acetylated and deacetylated structures.…”