Structures of the first intermediates of the visual cascade

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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.