SuperBiHelix method for predicting the pleiotropic ensemble of G-protein-coupled receptor conformations

Proceedings of the National Academy of Sciences of the United States of America
Jenelle K BrayCaitlin E Scott

Abstract

There is overwhelming evidence that G-protein-coupled receptors (GPCRs) exhibit several distinct low-energy conformations, each of which might favor binding to different ligands and/or lead to different downstream functions. Understanding the function of such proteins requires knowledge of the ensemble of low-energy configurations that might play a role in this pleiotropic functionality. We earlier reported the BiHelix method for efficiently sampling the (12)(7) = 35 million conformations resulting from 30° rotations about the axis (η) of all seven transmembrane helices (TMHs), showing that the experimental structure is reliably selected as the best conformation from this ensemble. However, various GPCRs differ sufficiently in the tilts of the TMHs that this method need not predict the optimum conformation starting from any other template. In this paper, we introduce the SuperBiHelix method in which the tilt angles (θ, ϕ) are optimized simultaneously with rotations (η) efficiently enough that it is practical and sufficient to sample (5 × 3 × 5)(7) = 13 trillion configurations. This method can correctly identify the optimum structure of a GPCR starting with the template from a different GPCR. We have validated this method by pre...Continue Reading

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Citations

Aug 27, 2014·Proceedings of the National Academy of Sciences of the United States of America·Ravinder AbrolChristopher Irons
Jan 13, 2016·Journal of Chemical Theory and Computation·Dimitar V PachovHenry van den Bedem
Dec 4, 2015·Journal of Chemical Information and Modeling·Caitlin ScottRavinder Abrol
Jun 6, 2015·Protein Science : a Publication of the Protein Society·Claire A de MarchJérôme Golebiowski
Jul 29, 2015·PLoS Computational Biology·Dimitar V Pachov, Henry van den Bedem
Nov 14, 2017·PLoS Computational Biology·Thomas CoudratPatrick M Sexton
Mar 5, 2020·Proceedings of the National Academy of Sciences of the United States of America·Amirhossein MafiWilliam A Goddard
Jul 1, 2020·Proceedings of the National Academy of Sciences of the United States of America·Amirhossein MafiWilliam A Goddard
Feb 3, 2015·Journal of Chemical Information and Modeling·Quanjie LiHongwei Tan
Sep 21, 2021·The Journal of Physical Chemistry Letters·Moon Young YangWilliam A Goddard

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