The Molecular Mechanism Underlying Ligand Binding to the Membrane-Embedded Site of a G-Protein-Coupled Receptor

doi:10.1021/acs.jctc.8b00046

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	The Molecular Mechanism Underlying Ligand Binding to the Membrane-Embedded Site of a G-Protein-Coupled Receptor
	Yuan, Xiaojing 2,3; Raniolo, Stefano 1; Limongelli, Vittorio 1,4; Xu, Yechun2,3
刊名	JOURNAL OF CHEMICAL THEORY AND COMPUTATION
	2018-05
卷号	14 期号:5 页码:2761-2770
ISSN号	1549-9618
DOI	10.1021/acs.jctc.8b00046
文献子类	Article
英文摘要	The crystal structure of P2Y(1) receptor (P2Y(1)R), a class A GPCR, revealed a special extra-helical site for its antagonist, BPTU, which locates in-between the membrane and the protein. However, due to the limitation of crystallization experiments, the membrane was mimicked by use of detergents, and the information related to the binding of BPTU to the receptor in the membrane environment is rather limited. In the present work, we conducted a total of similar to 7.5 mu s all-atom simulations in explicit solvent using conventional molecular dynamics and multiple enhanced sampling methods, with models of BPTU and a POPC bilayer, both in the absence and presence of P2Y(1)R. Our simulations revealed that BPTU prefers partitioning into the interface of polar/lipophilic region of the lipid bilayer before associating with the receptor. Then, it interacts with the second extracellular loop of the receptor and reaches the binding site through the lipid receptor interface. In addition, by use of funnel-metadynamics simulations which efficiently enhance the sampling of bound and unbound states, we provide a statistically accurate description of the underlying binding free energy landscape. The calculated absolute ligand receptor binding affinity is in excellent agreement with the experimental data (Delta G(b0_theo) = 11.5 kcal mol(-1), Delta G(b0_exp) = 11.7 kcal mol(-1)). Our study broadens the view of the current experimental/theoretical models and our understanding of the protein ligand recognition mechanism in the lipid environment. The strategy used in this work is potentially applicable to investigate ligands association/dissociation with other membrane-embedded sites, allowing identification of compounds targeting membrane receptors of pharmacological interest.
资助项目	National Key R&D Program of China[2017YFB0202604] ; National Key R&D Program of China[2016YFA0502301] ; National Natural Science Foundation of China[81422047] ; National Natural Science Foundation of China[81661148046] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase)[U1501501] ; European Cooperation in Science and Technology (COST Action)[CA15135] ; Swiss National Science Foundation[200021_163281]
WOS关键词	P2Y(1) RECEPTOR ; METADYNAMICS SIMULATIONS ; ALLOSTERIC MODULATORS ; FUNNEL-METADYNAMICS ; TARGET BINDING ; LIPID-BILAYER ; FORCE-FIELD ; IN-VIVO ; PATHWAY ; KINETICS
WOS研究方向	Chemistry ; Physics
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000431926500044
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279777]
专题	药物发现与设计中心
通讯作者	Xu, Yechun
作者单位	1.Univ Svizzera Italiana, Inst Computat Sci, Ctr Computat Med Cardiol, Fac Biomed Sci, CH-6900 Lugano, Switzerland; 2.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 4.Univ Naples Federico II, Dept Pharm, I-80131 Naples, Italy
推荐引用方式 GB/T 7714	Yuan, Xiaojing,Raniolo, Stefano,Limongelli, Vittorio,et al. The Molecular Mechanism Underlying Ligand Binding to the Membrane-Embedded Site of a G-Protein-Coupled Receptor[J]. JOURNAL OF CHEMICAL THEORY AND COMPUTATION,2018,14(5):2761-2770.
APA	Yuan, Xiaojing,Raniolo, Stefano,Limongelli, Vittorio,&Xu, Yechun.(2018).The Molecular Mechanism Underlying Ligand Binding to the Membrane-Embedded Site of a G-Protein-Coupled Receptor.JOURNAL OF CHEMICAL THEORY AND COMPUTATION,14(5),2761-2770.
MLA	Yuan, Xiaojing,et al."The Molecular Mechanism Underlying Ligand Binding to the Membrane-Embedded Site of a G-Protein-Coupled Receptor".JOURNAL OF CHEMICAL THEORY AND COMPUTATION 14.5(2018):2761-2770.