Mapping the Functional Binding Sites of Cholesterol in 尾2-Adrenergic Receptor by Long-Time Molecular Dynamics Simulations

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• 作者：Xiaohui Cang ; Yun Du ; Yanyan Mao ; Yuanyuan Wang ; Huaiyu Yang ; Hualiang Jiang
• 刊名：The Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：January 31, 2013
• 年：2013
• 卷：117
• 期：4
• 页码：1085-1094
• 全文大小：528K
• 年卷期：v.117,no.4(January 31, 2013)
• ISSN：1520-5207

文摘

Cholesterol, an abundant membrane component in both lipid rafts and caveolae of cell membrane, plays a crucial role in regulating the function and organization of various G-protein coupled receptors (GPCRs). However, the underlying mechanism for cholesterol-GPCR interaction is still unclear. To this end, we performed a series of microsecond molecular dynamics (MD) simulations on 尾₂-adrenergic receptor (尾₂AR) in the presence and absence of cholesterol molecules in the POPC bilayer. The unbiased MD simulation on the system with cholesterols reveals that cholesterol molecules can spontaneously diffuse to seven sites on the 尾₂AR surfaces, three in the extracellular leaflet (e1鈥揺3) and four in the intracellular leaflet (i1, i2, i4, and i5). The MD simulation identifies three cholesterol-binding sites (i2, e2, and e3) that are also observed in the crystal structures of several GPCRs. Cholesterol binding to site e1 lock Trp313^7.40 into a certain conformation that may facilitate ligand鈥搑eceptor binding, and cholesterol binding to site i2 provides a structural support for the reported cholesterol-mediate dimeric form of 尾₂AR (PDB code 2RH1). In addition, both competitive and cooperative effects between cholesterols and phospholipids in binding to 尾₂AR were observed in our MD simulations. Together, these results provide new insights into cholesterol鈥揋PCR interactions.