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Mechanism of Signal Propagation upon Retinal Isomerization: Insights from Molecular Dynamics Simulations of Rhodopsin Restrained by Normal Modes

Basak Isin ^*, Klaus Schulten  , Emad Tajkhorshid   and Ivet Bahar ^*

^* Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and Beckman Institute, Department of Physics, and Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois

Correspondence: Address reprint requests to Ivet Bahar, Dept. of Computational Biology, School of Medicine, University of Pittsburgh, 3501 Fifth Ave., Pittsburgh, PA 15260. Tel.: 412-648-3332; Fax: 412-648-3163; E-mail: bahar{at}ccbb.pitt.edu; http://www.ccbb.pitt.edu; or Emad Tajkhorshid, Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Tel.: 217-244-6914; Fax: 217-244-6078; E-mail: emad{at}life.uiuc.edu; http://www.mcb.uiuc.edu/.

As one of the best studied members of the pharmaceutically relevant family of G-protein-coupled receptors, rhodopsin serves as a prototype for understanding the mechanism of G-protein-coupled receptor activation. Here, we aim at exploring functionally relevant conformational changes and signal transmission mechanisms involved in its photoactivation brought about through a cis-trans photoisomerization of retinal. For this exploration, we propose a molecular dynamics simulation protocol that utilizes normal modes derived from the anisotropic network model for proteins. 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, consistent with interresidue interactions. We identify two highly stable regions in rhodopsin, one clustered near the chromophore, the other near the cytoplasmic ends of transmembrane helices H1, H2, and H7. Due to redistribution of interactions in the neighborhood of retinal 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 structures obtained by our simulations, 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.