A Unified Conformational Selection and Induced Fit Approach to Protein-Peptide Docking

Abstract

Protein-peptide interactions are vital for the cell. They mediate, inhibit or serve as structural components in nearly 40% of all macromolecular interactions, and are often associated with diseases, making them interesting leads for protein drug design. In recent years, large-scale technologies have enabled exhaustive studies on the peptide recognition preferences for a number of peptide-binding domain families. Yet, the paucity of data regarding their molecular binding mechanisms together with their inherent flexibility makes the structural prediction of protein-peptide interactions very challenging. This leaves flexible docking as one of the few amenable computational techniques to model these complexes. We present here an ensemble, flexible protein-peptide docking protocol that combines conformational selection and induced fit mechanisms. Starting from an ensemble of three peptide conformations (extended, a-helix, polyproline-II), flexible docking with HADDOCK generates 79.4% of high quality models for bound/unbound and 69.4% for unbound/unbound docking when tested against the largest protein-peptide complexes benchmark dataset available to date. Conformational selection at the rigid-body docking stage successfully recovers the most relevant conformation for a given protein-peptide complex and the subsequent flexible refinement further improves the interface by up to 4.5 Å interface RMSD. Cluster-based scoring of the models results in a selection of near-native solutions in the top three for ∼75% of the successfully predicted cases. This unified conformational selection and induced fit approach to protein-peptide docking should open the route to the modeling of challenging systems such as disorder-order transitions taking place upon binding, significantly expanding the applicability limit of biomolecular interaction modeling by docking.

Studying the binding interactions of allosteric agonists and antagonists of the CXCR4 receptor

“…This allows guiding the protein conformational search and, hence, the web server protocol 53 requires for each protein to specify a minimum number of residues involved in these interactions. HADDOCK uses a knowledge based method for driving the flexible docking which combines conformational selection and induced fit mechanisms 56 .…”

“…B HADDOCK best scored pose (left) for 3OE6 and the global results grouped in clusters (right). Score values are represented versus the ligand RMSD (l-RMSD)56 . C Final and stabilized conformation of ATI-2341-3OE6 obtained by MD simulation.…”

Local destabilization, rigid body, and fuzzy docking facilitate the phosphorylation of the transcription factor Ets-1 by the mitogen-activated protein kinase ERK2

“…These AIRs were used in docking calculations using HADDOCK (30,31) to generate the structure of the EtsΔ138 D hyd -site bound to the ERK2 DRS (Fig. 4A).…”

The NMR2 Method to Determine Rapidly the Structure of the Binding Pocket of a Protein–Ligand Complex with High Accuracy

“…Finally, the CSP-based methods also use a docking scoring protocol that relies on force fields or scoring function. The most popular program used in NMR is CSP-HADDOCK [40,47,60], which can make use of a large set of additional experimental restraints such as residual dipolar couplings or pseudocontact shifts [41,61,62]. Other docking programs are BiGGER [63], AutoDockFilter [64], SAMPLEX [65], and LIGDOCK [47].…”