Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

Abstract

Protein-peptide interactions are often associated with large-scale conformational changes that are difficult to study either by classical molecular modeling or by experiment. Recently, we have developed the CABS-dock method for flexible protein-peptide docking that enables large-scale rearrangements of the protein chain. In this study, we use CABS-dock to investigate the binding of the p53-MDM2 complex, an element of the cell cycle regulation system crucial for anti-cancer drug design. Experimental data suggest that p53-MDM2 binding is affected by significant rearrangements of a lid region - the N-terminal highly flexible MDM2 fragment; however, the details are not clear. The large size of the highly flexible MDM2 fragments makes p53-MDM2 intractable for exhaustive binding dynamics studies using atomistic models. We performed extensive dynamics simulations using the CABS-dock method, including large-scale structural rearrangements of MDM2 flexible regions. Without a priori knowledge of the p53 peptide structure or its binding site, we obtained near-native models of the p53-MDM2 complex. The simulation results match well the experimental data and provide new insights into the possible role of the lid fragment in p53 binding. The presented case study demonstrates that CABS-dock methodology opens up new opportunities for protein-peptide docking with large-scale changes of the protein receptor structure.

Highly Flexible Protein-Peptide Docking Using CABS-Dock

“…The CABS-dock web server (freely available at http://biocomp.chem.uw.edu.pl/CABSdock/) provides an interface for the CABS-dock method for protein-peptide docking together with up-to-date documentation and benchmark examples [15]. Several illustrative examples of CABS-dock applications have also been described in [16,21]. Here only the basic CABS-dock features are outlined.…”

“…Such high modeling efficiency is achieved thanks to the simulation engine based on the CABS prediction platform [17][18][19]. Alongside with the Rosetta platform [20], CABS currently offers perhaps the most efficient means for modeling significant conformational changes, successfully tested in protein-peptide on-the-fly docking [21].…”

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

“…CABS-dock uses a very efficient simulation approach, the CABS coarse-grained protein model (its broad applications in protein modeling, protein structure prediction, simulation of protein flexibility and disordered states have been recently summarized in the reviews [33][34][35]. CABS-dock has been first introduced as a web server [36][37][38] and successfully applied to modeling large-scale conformation changes of protein receptor during peptide binding [39], protein-protein docking [38], peptide docking using sparse information on protein-peptide residue-residue contacts [40] and modeling the cleavage events occurring during proteolytic peptide degradation [41]. Recently, CABS-dock has been made available as a standalone application [20], which contains many features and extensions for advanced users.…”

Protocols for all-atom reconstruction and high-resolution refinement of protein-peptide complex structures

“…CABS-dock is available as a web server [2] and standalone application [3]. CABSdock has been applied in numerous docking studies, including docking associated with largescale conformational transitions [12,13]. It has been also extended to modeling protocols that allow for residue-residue contact map analysis of the binding dynamics [14], prediction of protein-protein interaction interfaces [15] and docking using fragmentary information about protein-peptide residue-residue contacts [16].…”