Retinal Ligand Mobility Explains Internal Hydration and Reconciles Active Rhodopsin Structures

Biochemistry (Impact Factor: 3.38). 12/2013; 53(2). DOI: 10.1021/bi4013947
Source: PubMed

ABSTRACT 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 much attention due to 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 NMR 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 active-like crystal structures. Surprisingly, this elongation corresponds to both a dramatic influx of bulk water into the hydrophobic core of the protein and to 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.

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