Enhanced sampling of protein conformational states for dynamic cross‐docking within the protein‐protein docking server SwarmDock. Issue 8 (20th November 2019)

• Record Type: Journal Article
• Authors: Torchala, Mieczyslaw; Gerguri, Tereza; Chaleil, Raphael A. G.; Gordon, Patrick; Russell, Francis; Keshani, Miriam; Bates, Paul A.
• Is Part Of: Proteins. Volume 88:Issue 8(2020)
• Page Start: 962
• Page End: 972
• Publication Date: 2019-11-20
• Subjects: Aether Engine -- CAPRI -- conformational selection -- conformational states space sampling -- cross‐docking -- DFIRE2 -- induced fit -- normal modes -- protein‐protein docking -- protein‐protein interactions -- SwarmDock; Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.25851
• Languages: English
• ISSNs: 0887-3585

Abstract

Abstract: The formation of specific protein‐protein interactions is often a key to a protein's function. During complex formation, each protein component will undergo a change in the conformational state, for some these changes are relatively small and reside primarily at the sidechain level; however, others may display notable backbone adjustments. One of the classic problems in the protein‐docking field is to be able to a priori predict the extent of such conformational changes. In this work, we investigated three protocols to find the most suitable input structure conformations for cross‐docking, including a robust sampling approach in normal mode space. Counterintuitively, knowledge of the theoretically best combination of normal modes for unbound‐bound transitions does not always lead to the best results. We used a novel spatial partitioning library, Aether Engine (see Supplementary Materials ), to efficiently search the conformational states of 56 receptor/ligand pairs, including a recent CAPRI target, in a systematic manner and selected diverse conformations as input to our automated docking server, SwarmDock, a server that allows moderate conformational adjustments during the docking process. In essence, here we present a dynamic cross‐docking protocol, which when benchmarked against the simpler approach of just docking the unbound components shows a 10% uplift in the quality of the top docking pose.