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Article

Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods

Department of Chemistry and Biochemistry, California State University, Northridge, CA 91330, USA
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(21), 5290; https://doi.org/10.3390/ijms20215290
Received: 2 October 2019 / Revised: 17 October 2019 / Accepted: 24 October 2019 / Published: 24 October 2019
(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)
The neurotransmitter molecule acetylcholine is capable of activating five muscarinic acetylcholine receptors, M1 through M5, which belong to the superfamily of G-protein-coupled receptors (GPCRs). These five receptors share high sequence and structure homology; however, the M1, M3, and M5 receptor subtypes signal preferentially through the Gαq/11 subset of G proteins, whereas the M2 and M4 receptor subtypes signal through the Gαi/o subset of G proteins, resulting in very different intracellular signaling cascades and physiological effects. The structural basis for this innate ability of the M1/M3/M5 set of receptors and the highly homologous M2/M4 set of receptors to couple to different G proteins is poorly understood. In this study, we used molecular dynamics (MD) simulations coupled with thermodynamic analyses of M1 and M2 receptors coupled to both Gαi and Gαq to understand the structural basis of the M1 receptor’s preference for the Gαq protein and the M2 receptor’s preference for the Gαi protein. The MD studies showed that the M1 and M2 receptors can couple to both Gα proteins such that the M1 receptor engages with the two Gα proteins in slightly different orientations and the M2 receptor engages with the two Gα proteins in the same orientation. Thermodynamic studies of the free energy of binding of the receptors to the Gα proteins showed that the M1 and M2 receptors bind more strongly to their cognate Gα proteins compared to their non-cognate ones, which is in line with previous experimental studies on the M3 receptor. A detailed analysis of receptor–G protein interactions showed some cognate-complex-specific interactions for the M2:Gαi complex; however, G protein selectivity determinants are spread over a large overlapping subset of residues. Conserved interaction between transmembrane helices 5 and 6 far away from the G-protein-binding receptor interface was found only in the two cognate complexes and not in the non-cognate complexes. An analysis of residues implicated previously in G protein selectivity, in light of the cognate and non-cognate structures, shaded a more nuanced role of those residues in affecting G protein selectivity. The simulation of both cognate and non-cognate receptor–G protein complexes fills a structural gap due to difficulties in determining non-cognate complex structures and provides an enhanced framework to probe the mechanisms of G protein selectivity exhibited by most GPCRs. View Full-Text
Keywords: receptor–G protein interactions; molecular mechanics/Poisson–Boltzmann surface area (MMPBSA); allostery; membrane protein simulations; GPCR activation; molecular dynamics receptor–G protein interactions; molecular mechanics/Poisson–Boltzmann surface area (MMPBSA); allostery; membrane protein simulations; GPCR activation; molecular dynamics
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MDPI and ACS Style

Santiago, L.J.; Abrol, R. Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods. Int. J. Mol. Sci. 2019, 20, 5290. https://doi.org/10.3390/ijms20215290

AMA Style

Santiago LJ, Abrol R. Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods. International Journal of Molecular Sciences. 2019; 20(21):5290. https://doi.org/10.3390/ijms20215290

Chicago/Turabian Style

Santiago, Luis J., and Ravinder Abrol. 2019. "Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods" International Journal of Molecular Sciences 20, no. 21: 5290. https://doi.org/10.3390/ijms20215290

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