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PMID: 17719606 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Dynamic structure of retinylidene ligand of rhodopsin probed by molecular simulations.

Journal of molecular biology ·Vol. 372 ·No. 4 ·2007-09-28 ·Pages 906-917

Lau PW, Grossfield A, Feller SE, Pitman MC, Brown MF

Abstract

Rhodopsin is currently the only available atomic-resolution template for understanding biological functions of the G protein-coupled receptor (GPCR) family. The structural basis for the phenomenal dark state stability of 11-cis-retinal bound to rhodopsin and its ultrafast photoreaction are active topics of research. In particular, the beta-ionone ring of the retinylidene inverse agonist is crucial for the activation mechanism. We analyzed a total of 23 independent, 100 ns all-atom molecular dynamics simulations of rhodopsin embedded in a lipid bilayer in the microcanonical (N,V,E) ensemble. Analysis of intramolecular fluctuations predicts hydrogen-out-of-plane (HOOP) wagging modes of retinal consistent with those found in Raman vibrational spectroscopy. We show that sampling and ergodicity of the ensemble of simulations are crucial for determining the distribution of conformers of retinal bound to rhodopsin. The polyene chain is rigidly locked into a single, twisted conformation, consistent with the function of retinal as an inverse agonist in the dark state. Most surprisingly, the beta-ionone ring is mobile within its binding pocket; interactions are non-specific and the cavity is sufficiently large to enable structural heterogeneity. We find that retinal occupies two distinct conformations in the dark state, contrary to most previous assumptions. The beta-ionone ring can rotate relative to the polyene chain, thereby populating both positively and negatively twisted 6-s-cis enantiomers. This result, while unexpected, strongly agrees with experimental solid-state (2)H NMR spectra. Correlation analysis identifies the residues most critical to controlling mobility of retinal; we find that Trp265 moves away from the ionone ring prior to any conformational transition. Our findings reinforce how molecular dynamics simulations can challenge conventional assumptions for interpreting experimental data, especially where existing models neglect conformational fluctuations.

MeSH Terms
Binding Sites Computer Simulation Hydrogen/chemistry Ligands Models, Molecular Molecular Structure Nuclear Magnetic Resonance, Biomolecular Protein Structure, Tertiary Retinal Pigments/chemistry,metabolism Retinaldehyde/chemistry,metabolism Retinoids/chemistry,metabolism Rhodopsin/chemistry,metabolism
Chemicals
Ligands Retinal Pigments Retinoids retinylidene chromophore Hydrogen Rhodopsin Retinaldehyde
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lau Pick-Wei
Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, AZ 85721, USA.
Grossfield Alan
IBM TJ Watson Research Center, Yorktown Heights, NY 10598, USA.
Feller Scott E
Department of Chemistry, Wabash College, Crawfordsville, IN 47933, USA.
Pitman Michael C
IBM TJ Watson Research Center, Yorktown Heights, NY 10598, USA.
Brown Michael F
Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, AZ 85721, USA; Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA; Department of Physics, University of Arizona, Tucson, AZ 85721, USA. Electronic address: mfbrown@u.arizona.edu.
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Article Info
Journal
Journal of molecular biology
Abbr.
J Mol Biol
ISSN
0022-2836
DOI
10.1016/j.jmb.2007.06.047
Email
mfbrown@u.arizona.edu
Published
2007-09-28
Epub
2007-00-26
Pages
906-917
Language
English
Region
England
NLM ID
2985088R
PMCID
PMC5233727
Subset
IM
Grants
NEI NIH HHS · R01 EY012049 · United States
NEI NIH HHS · EY12049 · United States
External Links
PubMed source DOI: 10.1016/j.jmb.2007.06.047 PMC Full Text View journal details
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