Understanding molecular recognition of small molecules by proteins in atomistic detail is key for drug design. Molecular docking is a widely used computational method to mimic ligand-protein association in silico. However, predicting conformational changes occurring in proteins upon ligand binding is still a major challenge. Ensemble docking approaches address this issue by considering a set of different conformations of the protein obtained either experimentally or from computer simulations, e.g. from molecular dynamics. However, holo structures prone to host (the correct) ligands are generally poorly sampled by standard molecular dynamics simulations of the unbound (apo) protein. In order to address this limitation, we introduce a computational approach based on metadynamics simulations called ensemble docking with enhanced sampling of pocket shape (EDES) that allows holo-like conformations of proteins to be generated by exploiting only their apo structures. This is achieved by defining a set of collective variables able to sample different shapes of the binding site, ultimately mimicking the steric effect due to the ligand. In this work, we assessed the method on re-docking and cross-docking calculations. In first case, we selected three different protein targets undergoing different extent of conformational changes upon binding and, for each of them, we docked the experimental ligand conformation into an ensemble of receptor structures generated by EDES. In the second case, in the contest of a blind docking challenge, we generated the 3D structures of a set of different ligands of the same receptor and docked them into a set of EDES-generated conformations of that receptor. In all cases, for both re-docking and cross-docking experiments, our protocol generates a significant fraction of structures featuring a low RMSD from the experimental holo geometry of the receptor. Moreover, ensemble docking calculations using those conformations yielded in almost all cases to native-like poses among the top-ranked ones. Finally, we also tested an improved EDES recipe on a further target, known to be extremely challenging due to its extended binding region and the large extent of conformational changes accompanying the binding of its ligands.
|Titolo:||An enhanced-sampling MD-based protocol for molecular docking|
|Data di pubblicazione:||4-feb-2020|
|Tipologia:||8.1 Tesi di Dottorato|