期刊
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
卷 14, 期 8, 页码 4467-4473出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jctc.8b00216
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资金
- German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) [CO 1715/1-1]
- French National Research Agency (Agence Nationale de la Recherche, ANR)
- U.S. National Science Foundation (NSF) as part of the Collaborative Research in Computational Neuroscience
- French government, through the UCAJEDI Investments in the Future project [ANR-15-IDEX-01]
A replica-exchange protocol remarkably enhances the sampling of the activation dynamics of the neurotensin receptor type 1, a G protein-coupled receptor (GPCR) and important drug target. Our work highlights the dynamic communication between conformational changes of the agonist and the G protein-binding site, via contraction-oscillation of the orthosteric pocket. It also gives insights into the mechanism by which certain mutations diminish or stimulate activation. The replica-exchange protocol effectively enhances barrier crossing where standard brute-force molecular dynamics simulations fail. It is readily applicable to other GPCRs and represents a promising approach for virtual ligand screening, using the typical features of receptor activation as a benchmark.
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