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Mechanistic insights into peptide and ligand binding of ATAD2-bromodomain via atomistic simulations disclose a role of induced fit and conformational selection

Abstract

ATAD2 has emerged as a promising bromodomain (BRD)-containing therapeutic drug target in multiple human cancers. However, recent druggability assessment studies predicted ATAD2’s BRD as a target ‘difficult to drug’ because its binding pocket possesses structural features that are unfeasible for ligand binding. Here, by using all-atom molecular dynamics simulations and an advanced metadynamics method, we demonstrate a dynamic view of the binding pocket features which can hardly be obtained from the “static” crystal data. The most important features disclosed from our simulations data, include: (1) a distinct ‘open-to-closed’ conformational switch of the ZA loop region in the context of peptide or ligand binding, akin to the induced fit mechanism of molecular recognition, (2) a dynamic equilibrium of the BC loop “in” and “out” conformations, highlighting a role in the conformational selection mechanism for ligand binding, and (3) a new binding region identified distal to the histone-binding pocket that might have implications in bromodomain biology and in inhibitor development. Moreover, based on our simulation results, we propose a model for an “auto-regulatory” mechanism of ATAD2’s BRD for histone binding. Overall, the results of this study will not only have implications in bromodomain biology but also provide a theoretical basis for the discovery of new ATAD2’s BRD inhibitors.

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Supplementary files

Publication details

The article was received on 18 Jun 2018, accepted on 08 Aug 2018 and first published on 08 Aug 2018


Article type: Paper
DOI: 10.1039/C8CP03860K
Citation: Phys. Chem. Chem. Phys., 2018, Accepted Manuscript
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    Mechanistic insights into peptide and ligand binding of ATAD2-bromodomain via atomistic simulations disclose a role of induced fit and conformational selection

    Y. Zhou, M. Hussain, G. Kuang, J. Zhang and Y. Tu, Phys. Chem. Chem. Phys., 2018, Accepted Manuscript , DOI: 10.1039/C8CP03860K

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