title: Mapping the functional binding sites of cholesterol in β2-adrenergic receptor by long-time molecular dynamics simulations.
abstract: 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 β(2)-adrenergic receptor (β(2)AR) 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 β(2)AR surfaces, three in the extracellular leaflet (e1-e3) 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-receptor binding, and cholesterol binding to site i2 provides a structural support for the reported cholesterol-mediate dimeric form of β(2)AR (PDB code 2RH1). In addition, both competitive and cooperative effects between cholesterols and phospholipids in binding to β(2)AR were observed in our MD simulations. Together, these results provide new insights into cholesterol-GPCR interactions.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Cang
authors.forename: Yun
authors.initials: Y
authors.lastname: Du
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Mao
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D001665:Binding Sites; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism*; D013997:Time Factors
chemical_list: D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D002784:Cholesterol