Retinal ligand mobility explains internal hydration and reconciles active rhodopsin structures

Biochemistry. 2014 Jan 21;53(2):376-85. doi: 10.1021/bi4013947. Epub 2014 Jan 8.


Rhodopsin, the mammalian dim-light receptor, is one of the best-characterized G-protein-coupled receptors, a pharmaceutically important class of membrane proteins that has garnered a great deal of attention because of the recent availability of structural information. Yet the mechanism of rhodopsin activation is not fully understood. Here, we use microsecond-scale all-atom molecular dynamics simulations, validated by solid-state (2)H nuclear magnetic resonance spectroscopy, to understand the transition between the dark and metarhodopsin I (Meta I) states. Our analysis of these simulations reveals striking differences in ligand flexibility between the two states. Retinal is much more dynamic in Meta I, adopting an elongated conformation similar to that seen in the recent activelike crystal structures. Surprisingly, this elongation corresponds to both a dramatic influx of bulk water into the hydrophobic core of the protein and a concerted transition in the highly conserved Trp265(6.48) residue. In addition, enhanced ligand flexibility upon light activation provides an explanation for the different retinal orientations observed in X-ray crystal structures of active rhodopsin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Crystallography, X-Ray
  • Ligands
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Nuclear Magnetic Resonance, Biomolecular
  • Retinaldehyde / chemistry*
  • Retinaldehyde / metabolism
  • Rhodopsin / chemistry*
  • Rhodopsin / metabolism
  • Time Factors
  • Water / chemistry
  • Water / metabolism


  • Ligands
  • Water
  • Rhodopsin
  • Retinaldehyde