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Proposing Institution

Karlsruher Institute of Technology
Project Manager

Prof. Dr. Wolfgang Wenzel
Hermann-von-Helmholtz-Platz 1
76344 Eggenstein-Leopoldshafen
The ability of a cell to react to extracellular stimuli is enabled by a complex protein machinery attached to the cell membrane. The core of this machinery consists of transmembrane proteins termed G protein-coupled receptors and their associated G proteins found in the cell interior. This project aims at deciphering the pathways and the underlying free-energy landscapes of the binding and unbinding processes between a G protein and a prominent G-protein coupled receptor, β2-adrenergic receptor, at different stages of the activation cycle and in various membrane environments. The results are expected to provide new important details on the mechanism of signal transmission from the cell exterior to the cell interior and its modulation by membrane composition.Using atomistic molecular dynamics simulations we will address the assembly, the structure, and the stability of the signaling complex before and after receptor activation and the stability of the intermediate complex. Simulations will deliver molecular determinants of the G protein-exerted effects on the receptor and an atomistic view on the (un)binding pathways. Moreover, by systematically varying the membrane composition both specific and unspecific effects of different lipids and cholesterol on the interactions between the receptor and the G protein will be elucidated. Complementary multifunctional atomic force microscopy imaging, performed by the group of Prof. Daniel Müller at ETH-Zürich, will be used to obtain binding force profiles of the G protein to the receptor along the dissociation/association pathways. Moreover, dynamic single-molecule force spectroscopy will be applied to study (de)stabilization effects of the G protein on the receptor at different stages of the activation cycle.This collaborative effort - combining molecular dynamics simulations and atomic force miscroscopy - aims to provide first information at atomistic resolution on the assembly and disassembly of the G protein-coupled receptor/G protein signaling complex and lipid modulation effect thereon.

Impressum, Conny Wendler