Structures of the first intermediates of the visual cascade

g蛋白偶联受体（gpcr）是七螺旋跨膜蛋白中最大的家族。对于跨细胞膜的信号转导至关重要，它们影响各种各样的生理过程。视紫红质是一种典型的GPCR，负责脊椎动物的暗视。它也是唯一一种晶体结构已经确定的GPCR，提供了其配体11-顺式视网膜的原子细节结构，以及它如何与蛋白质结合。配体激发转化为视紫红质活化并偶联到g蛋白的机制的阐明可能成为GPCR组其他成员的结构和功能的示范。尽管从视紫红质的静息状态中获得了信息，但随后的视觉级联中间反应仍然是一个谜。深紫红质是光激发后的中间体，存在晶体结构，但尚未公开。对于Meta - 1中间低分辨率低温电子显微图像已发表。本建议的目的有三个方面：验证，并在必要时改进已报道的结构，特别是关于配体构象，采用高质量的从头算方法，在必要和可能的情况下，由经典力场方法支持；其次，通过从头算分子动力学，在基态和激发态势能面建立碱基中间体的结构模型。最后，根据现有的构造和间接证据，建立后期中间体的构造模型。在这些结构的基础上，中间体的性质将在其他项目中进行研究，动力学模型将被开发出来，以全面描述视觉级联的初始阶段。

G-protein-coupled receptors (GPCRs) constitute the largest family of heptahelical transmembrane proteins. Essential for signal transduction across cell membranes they affect a broad variety of physiological processes. Rhodopsin is a prototypical GPCR which is responsible for scotopic vision in vertebrate species. lt is also the only GPCR for which the crystal structure has been determined providing in atomic detail the structure of its ligand, 11-cis-retinal, and how it fits into the protein. Elucidation of the mechanism, by which ligand excitation is transformed into rhodopsin activation and coupling to the G-protein may become exemplary for the structure and function of other members of the GPCR group.Despite the information gained from the resting state of rhodopsin the ensuing intermediates of the visual cascade remain an enigma. For bathorhodopsin which is the intermediate directly following photoexcitation a crystal structure exists, but has not been made public. For the Meta 1 intermediate low-resolution cryoelectron microscopic images have published. The aim of the present proposal is threefold: verify, and if necessary improve the reported structures, especially with respect to the ligand conformation, by employing high-quality ab initio methods supported, where necessary and possible, by classical force field methods; secondly, develop structural models for the batho intermediate by performing ab initio molecular dynamics an both the ground and the excited state potential energy surfaces. Finally, structural models for the later intermediates will be developed based an the available structures and indirect evidence.On the basis of these structures the properties of the intermediates will be studied in other projects, and dynamical models will be developed to arrive at a comprehensive description of the initial stages of the visual cascade.