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J Chem Theory Comput. 2020 Mar 9. doi: 10.1021/acs.jctc.9b01136. [Epub ahead of print]

Characterizing Interhelical Interactions of G-Protein Coupled Receptors with the Fragment Molecular Orbital Method.

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Evotec (U.K.) Ltd., 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, United Kingdom.
Institute of Structural & Molecular Biology, Research Department of Structural & Molecular Biology, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom.
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.
CD-FMat, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan.
Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.


G-protein coupled receptors (GPCRs) are the largest superfamily of membrane proteins, regulating almost every aspect of cellular activity and serving as key targets for drug discovery. We have identified an accurate and reliable computational method to characterize the strength and chemical nature of the interhelical interactions between the residues of transmembrane (TM) domains during different receptor activation states, something that cannot be characterized solely by visual inspection of structural information. Using the fragment molecular orbital (FMO) quantum mechanics method to analyze 35 crystal structures representing different branches of the class A GPCR family, we have identified 69 topologically equivalent TM residues that form a consensus network of 51 inter-TM interactions, providing novel results that are consistent with and help to rationalize experimental data. This discovery establishes a comprehensive picture of how defined molecular forces govern specific interhelical interactions which, in turn, support the structural stability, ligand binding, and activation of GPCRs.


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