Prediction of the receptor conformation for iGluR2 agonist binding: QM/MM docking to an extensive conformational ensemble generated using normal mode analysis

Journal of Molecular Graphics & Modelling
Tommy SanderThomas Balle

Abstract

Highly flexible proteins constitute a significant challenge in molecular docking within the field of drug design. Depending on the efficacy of the bound ligand, the ligand-binding domain (LBD) of the ionotropic glutamate receptor iGluR2 adopts markedly different degrees of domain closure due to large-scale domain movements. With the purpose of predicting the induced domain closure of five known iGluR2 partial to full agonists we performed a validation study in which normal mode analysis (NMA) was employed to generate a 25-membered ensemble of iGluR2 LBD structures with gradually changing domain closures, followed by accurate QM/MM docking to the ensemble. Based on the docking scores we were able to predict the correct optimal degree of closure for each ligand within 1-3 degrees deviation from the experimental structures. We demonstrate that NMA is a useful tool for reliable ensemble generation and that we are able to predict the ligand induced conformational change of the receptor through docking to such an ensemble. The described protocol expands and improves the information that can be obtained from computational docking when dealing with a flexible receptor.

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Citations

Jun 8, 2011·Journal of Molecular Modeling·Jing LiuLing Yang
May 13, 2009·Journal of Chemical Information and Modeling·Manuel RuedaRuben Abagyan
Dec 15, 2010·International Journal of Molecular Sciences·Iain H Moal, Paul A Bates
Oct 5, 2010·Journal of Molecular Graphics & Modelling·Tommy SanderThomas Balle
Feb 3, 2009·Drug Discovery Today·Chandrika B-RaoSomesh D Sharma
Sep 23, 2014·European Journal of Medicinal Chemistry·Giulia PalermoMarco De Vivo
May 23, 2009·Journal of Chemical Information and Modeling·M Paul Gleeson, Duangkamol Gleeson

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