BP-Dock: A Flexible Docking Scheme for Exploring Protein–Ligand Interactions Based on Unbound Structures

Citations Over TimeTop 10% of 2013 papers

Abstract

Molecular docking serves as an important tool in modeling protein-ligand interactions. However, it is still challenging to incorporate overall receptor flexibility, especially backbone flexibility, in docking due to the large conformational space that needs to be sampled. To overcome this problem, we developed a novel flexible docking approach, BP-Dock (Backbone Perturbation-Dock) that can integrate both backbone and side chain conformational changes induced by ligand binding through a multi-scale approach. In the BP-Dock method, we mimic the nature of binding-induced events as a first-order approximation by perturbing the residues along the protein chain with a small Brownian kick one at a time. The response fluctuation profile of the chain upon these perturbations is computed using the perturbation response scanning method. These response fluctuation profiles are then used to generate binding-induced multiple receptor conformations for ensemble docking. To evaluate the performance of BP-Dock, we applied our approach on a large and diverse data set using unbound structures as receptors. We also compared the BP-Dock results with bound and unbound docking, where overall receptor flexibility was not taken into account. Our results highlight the importance of modeling backbone flexibility in docking for recapitulating the experimental binding affinities, especially when an unbound structure is used. With BP-Dock, we can generate a wide range of binding site conformations realized in nature even in the absence of a ligand that can help us to improve the accuracy of unbound docking. We expect that our fast and efficient flexible docking approach may further aid in our understanding of protein-ligand interactions as well as virtual screening of novel targets for rational drug design.

Related Papers

• → CB-Dock2: improved protein–ligand blind docking by integrating cavity detection, docking and homologous template fitting(2022)1,538 cited
• → Ligand−Protein Docking with Water Molecules(2008)150 cited
• → Towards Ligand Docking Including Explicit Interface Water Molecules(2013)78 cited
• → CSAlign and CSAlign-Dock: Structure alignment of ligands considering full flexibility and application to protein–ligand docking(2022)14 cited
• → A Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding(2020)1 cited