Retinal Ligand Mobility Explains Internal Hydration and Reconciles Active Rhodopsin Structures

• Published in: Biochemistry (Easton) Vol. 53; no. 2; pp. 376 - 385
• Main Authors: Leioatts, Nicholas, Mertz, Blake, Martínez-Mayorga, Karina, Romo, Tod D, Pitman, Michael C, Feller, Scott E, Grossfield, Alan, Brown, Michael F
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21.01.2014
• Subjects: 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
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi4013947

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 2H 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 Trp2656.48 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.