Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics
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 var...
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| Veröffentlicht in: | Physical chemistry chemical physics : PCCP 2014-01, Vol.16 (14), p.6398-6406 |
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| creator | Miao, Yinglong Nichols, Sara E McCammon, J Andrew |
| description | 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 Arg(3.50)-Glu(6.30) ionic lock, the Trp(6.48) toggle switch and the hydrogen interactions between Tyr(5.58)-Tyr(7.53). |
| doi_str_mv | 10.1039/c3cp53962h |
| format | Article |
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Free energy profiles of important structural motifs that undergo conformational transitions upon GPCR activation and allosteric signaling are analyzed in detail, including the Arg(3.50)-Glu(6.30) ionic lock, the Trp(6.48) toggle switch and the hydrogen interactions between Tyr(5.58)-Tyr(7.53).</description><identifier>ISSN: 1463-9076</identifier><identifier>EISSN: 1463-9084</identifier><identifier>DOI: 10.1039/c3cp53962h</identifier><identifier>PMID: 24445284</identifier><language>eng</language><publisher>England</publisher><subject>Allosteric Regulation ; Cellular ; Diseases ; Free energy ; Heart rate ; Heart Rate - physiology ; Humans ; Hydrogen Bonding ; Landscapes ; Molecular dynamics ; Molecular Dynamics Simulation ; Muscle Contraction - physiology ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - physiology ; Neurotransmitters ; Protein Structure, Tertiary ; Receptor, Muscarinic M2 - chemistry ; Receptor, Muscarinic M2 - metabolism ; Receptors ; Signal Transduction ; Thermodynamics</subject><ispartof>Physical chemistry chemical physics : PCCP, 2014-01, Vol.16 (14), p.6398-6406</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c500t-d79f6c46de23230daa9ba8f4a5809df9f6d2e2e63cdaec39a5469c6fe98f0b973</citedby><cites>FETCH-LOGICAL-c500t-d79f6c46de23230daa9ba8f4a5809df9f6d2e2e63cdaec39a5469c6fe98f0b973</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24445284$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miao, Yinglong</creatorcontrib><creatorcontrib>Nichols, Sara E</creatorcontrib><creatorcontrib>McCammon, J Andrew</creatorcontrib><title>Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics</title><title>Physical chemistry chemical physics : PCCP</title><addtitle>Phys Chem Chem Phys</addtitle><description>G-protein coupled receptors (GPCRs) mediate cellular responses to various hormones and neurotransmitters and are important targets for treating a wide spectrum of diseases. 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Free energy profiles of important structural motifs that undergo conformational transitions upon GPCR activation and allosteric signaling are analyzed in detail, including the Arg(3.50)-Glu(6.30) ionic lock, the Trp(6.48) toggle switch and the hydrogen interactions between Tyr(5.58)-Tyr(7.53).</description><subject>Allosteric Regulation</subject><subject>Cellular</subject><subject>Diseases</subject><subject>Free energy</subject><subject>Heart rate</subject><subject>Heart Rate - physiology</subject><subject>Humans</subject><subject>Hydrogen Bonding</subject><subject>Landscapes</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Muscle Contraction - physiology</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Myocytes, Cardiac - physiology</subject><subject>Neurotransmitters</subject><subject>Protein Structure, Tertiary</subject><subject>Receptor, Muscarinic M2 - chemistry</subject><subject>Receptor, Muscarinic M2 - metabolism</subject><subject>Receptors</subject><subject>Signal Transduction</subject><subject>Thermodynamics</subject><issn>1463-9076</issn><issn>1463-9084</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkM1KxDAUhYMozji68QEkSxGraZKmzVIGZxQG3Oi6psmNVtqmJi3Ytzcy47h1df8-DucehM5TcpMSJm81033GpKDvB2iecsESSQp-uO9zMUMnIXwQQtIsZcdoRjnnGS34HL2uPACGDvzbhBvVmaBVD9hZvE567waoO6zd2DdgsAcN_eB8uMbw1TfOx101YaU1NODVEMfWNaDHRnlspk61tQ6n6MiqJsDZri7Qy-r-efmQbJ7Wj8u7TaIzQobE5NIKzYUByigjRilZqcJylRVEGhuPhgIFwbRRoJlUGRdSCwuysKSSOVugy61udP05QhjKtg7RWPwJ3BjKNKNEsiIX6T9QkucxTsojerVFtXcheLBl7-tW-alMSfkTfvkXfoQvdrpj1YLZo79ps2_P0oES</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>Miao, Yinglong</creator><creator>Nichols, Sara E</creator><creator>McCammon, J Andrew</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7SC</scope><scope>7U5</scope><scope>8FD</scope><scope>JQ2</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope></search><sort><creationdate>20140101</creationdate><title>Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics</title><author>Miao, Yinglong ; 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| ispartof | Physical chemistry chemical physics : PCCP, 2014-01, Vol.16 (14), p.6398-6406 |
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| language | eng |
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| source | MEDLINE; Royal Society Of Chemistry Journals; Alma/SFX Local Collection |
| subjects | Allosteric Regulation Cellular Diseases Free energy Heart rate Heart Rate - physiology Humans Hydrogen Bonding Landscapes Molecular dynamics Molecular Dynamics Simulation Muscle Contraction - physiology Myocytes, Cardiac - cytology Myocytes, Cardiac - physiology Neurotransmitters Protein Structure, Tertiary Receptor, Muscarinic M2 - chemistry Receptor, Muscarinic M2 - metabolism Receptors Signal Transduction Thermodynamics |
| title | Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics |
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