Mechanism of Signal Propagation upon Retinal Isomerization: Insights from Molecular Dynamics Simulations of Rhodopsin Restrained by Normal Modes
Basak Isin 1, Klaus Schulten 2, Emad Tajkhorshid 3 and Ivet Bahar 1*
1 University of Pittsburgh
2 University of Illinois 3143 Beckman Institute
3 University of Illinois at Urbana-Champaign
* To whom correspondence should be addressed. E-mail: bahar{at}pitt.edu.
Submitted on August 29, 2007
Revised on September 24, 2007
Accepted on 12 March 2008
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Abstract |
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As one of the best studied members 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 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 inter-residue 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.
Key Words:
Anisotropic network model, G-protein coupled receptors, collective mode, light activation, steered MD simulations
