STRUCTURAL STUDIES OF G-PROTEIN COUPLED RECEPTORS DIMERS USING DISCRETE REPRESE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 对G蛋白偶联受体(GPCR二聚/寡聚)结构特征的探讨还处于起步阶段。计算和实验都试图揭示GPCR二聚体中蛋白质相互作用的基础，以及可能与作用机制有关的动态性质。从最近原子力显微镜图谱中的视紫红质分子在其天然的小鼠盘膜中的推断(梁等人，J.Biol。化学。2003年，278：21655-21662)表明视紫红质被组织成二聚体的二维阵列，跨膜(TM)螺旋4和5参与传统内接触。我们的计划是对最近提出的TM4，5-TM4，5视紫红质二聚体的分子模型进行详细的分子动力学(MD)模拟，该分子模型位于包含20？16？2个POPC分子的棕榈酰-油酰-磷脂酰胆碱(POPC)脂质双层膜的一个大单元细胞内(a=160？b=124？，c=98？)。模拟的结果将与对视紫红质单体进行的平行计算的结果进行比较，目的是确定在纳秒范围内具有高灵活性的结构域，这些结构域可能在齐聚方面具有重要的功能。在分子膜环境的有意义的显式表示下，关于二聚体体系结构松弛的推论可以推广到同一家族中的其他GPCR，对于这些GPCR，只有同源模型可用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Exploration of the structural features of G-protein coupled receptor (GPCR) dimerization/oligomerization is at its very beginning. Both computation and experiment seek to reveal the basis of protein interactions in GPCR dimers, and the dynamic properties that may relate to the functional mechanisms. Inferences from a recent atomic-force microscopy map of rhodopsin molecules in their native mouse disk membranes (Liang et al., J. Biol. Chem. 2003, 278:21655-21662) suggest that rhodopsin is organized into two-dimensional arrays of dimers, with the transmembrane (TM) helices 4 and 5 involved in intradimeric contact. Our plan is to carry out a detailed molecular dynamics (MD) simulation of the recently proposed molecular model of the TM4,5-TM4,5 rhodopsin dimer within a large unit cell (a=160 ¿ b= 124 ¿ and c= 98 ¿) of a hydrated patch of palmitoyl-oleoyl-phosphatidyl choline (POPC) lipid bilayer membrane containing 20 ¿ 16 ¿ 2 POPC molecules. Results from this simulation will be compared with those from parallel calculations performed on the rhodopsin monomer with the goal of identifying domains of high flexibility in the nanosecond range that may be functionally important with regard to oligomerization. The inferences concerning structural relaxation of the dimeric system within a meaningful explicit representation of the molecular membrane environment are generalizable to other GPCRs in the same family, for which only homology models are available.