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Issue 14, 2014
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Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics

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Abstract

G-protein coupled receptors (GPCRs) mediate cellular responses to various hormones and neurotransmitters and are important targets for treating a wide spectrum of diseases. They are known to adopt multiple conformational states (e.g., inactive, intermediate and active) during their modulation of various cell signaling pathways. Here, the free energy landscape of GPCRs is explored using accelerated molecular dynamics (aMD) simulations as demonstrated on the M2 muscarinic receptor, a key GPCR that regulates human heart rate and contractile forces of cardiomyocytes. Free energy profiles of important structural motifs that undergo conformational transitions upon GPCR activation and allosteric signaling are analyzed in detail, including the Arg3.50–Glu6.30 ionic lock, the Trp6.48 toggle switch and the hydrogen interactions between Tyr5.58–Tyr7.53.

Graphical abstract: Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics

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Publication details

The article was received on 18 Sep 2013, accepted on 14 Jan 2014 and first published on 14 Jan 2014


Article type: Paper
DOI: 10.1039/C3CP53962H
Citation: Phys. Chem. Chem. Phys., 2014,16, 6398-6406
  • Open access: Creative Commons BY license
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    Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics

    Y. Miao, S. E. Nichols and J. A. McCammon, Phys. Chem. Chem. Phys., 2014, 16, 6398
    DOI: 10.1039/C3CP53962H

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