A Robust Induced Fit Docking Approach with the Combination of the Hybrid All-Atom/United-Atom/Coarse-Grained Model and Simulated Annealing

Molecular docking remains an indispensable tool in computational biology and structure-based drug discovery. However, the correct prediction of binding poses remains a major challenge for molecular docking, especially for target proteins where a substrate binding induces significant reorganization of the active site. Here, we introduce an Induced Fit Docking (IFD) approach named AA/UA/CG-SA-IFD, which combines a hybrid All-Atom/United-Atom/Coarse-Grained model with Simulated Annealing. In this approach, the core region is represented by the All-Atom(AA) model, while the protein environment beyond the core region and the solvent are treated with either the United-Atom (UA) or the Coarse-Grained (CG) model. By combining the Elastic Network Model (ENM) for the CG region, the hybrid model ensures a reasonable description of ligand binding and the environmental effects of the protein, facilitating highly efficient and reliable sampling of ligand binding through Simulated Annealing (SA) at a high temperature. Upon validation with two testing sets, the AA/UA/CG-SA-IFD approach demonstrates remarkable accuracy and efficiency in induced fit docking, even for challenging cases where the docked poses significantly deviate from crystal structures.