TCB Publications - Abstract

Basak Isin, Klaus Schulten, Emad Tajkhorshid, and Ivet Bahar. Mechanism of signal propagation upon retinal isomerization: Insights from molecular dynamics simulations of rhodopsin restrained by normal modes. Biophysical Journal, 95:789-803, 2008. (PMC: 2440475)

ISIN2008 As the only structurally resolved member of the pharmaceutically relevant family of G-protein-coupled receptors (GPCRs), rhodopsin serves as a prototype for understanding the mechanism of GPCR activation. Here, we aim at exploring functionally relevant conformational changes and signal transmission mechanisms involved in its photoactivation. To this aim, we propose a molecular dynamics simulation protocol that utilizes normal modes derived from anisotropic network model. Deformations along multiple low frequency modes of motion are used to efficiently sample collective conformational changes in the presence of explicit membrane and water environment, in consistency with inter-residue interactions indicated by experimental data. We identified two highly stable regions, one clustered near the chromophore, and the other near the cytoplasmic ends of transmembrane helices H1, H2, and H7. Due to redistribution of interactions in the neighborhood of the chromophore upon stabilization of the trans form, local structural rearrangements in the adjoining H3-H6 residues are efficiently propagated to the cytoplasmic end of these particular helices. In the proposed activated state, all-trans-retinal interacts with Cys167 on H4 and Phe203 on H5, which were not accessible in the dark state, and exhibits stronger interactions with H5, while some of the contacts made (in the cis-form) with H6 are lost.

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