Functional Water Molecules in Rhodopsin Activation

G-protein-coupled
receptors (GPCRs) are integral membrane proteins
that mediate cellular response to an extensive variety of extracellular
stimuli. Studies of rhodopsin, a prototype GPCR, have suggested that
water plays an important role in mediating the activation of family
A GPCRs. However, our understanding of the function of water molecules
in the GPCR activation is still rather limited because resolving the
functional water molecules solely based on the results from existing
experiments is challenging. Using all-atom molecular dynamics simulations
in combination with inhomogeneous fluid theory, we identify in this
work the positioning of functional water molecules in the inactive
state, the Meta II state, and the constitutive active state of rhodopsin,
basing on the thermodynamic signatures of the water molecules. We
find that one hydration site likely functions as a switch to regulate
the distance between Glu181 and the Schiff base in the rhodopsin activation.
We observe that water molecules adjacent to the “NpxxY”
motif are not as stable in the Meta II state as in the inactive state
as indicated by the thermodynamics signatures, and we rationalize
that the behaviors of these water molecules are closely correlated
with the rearrangement of the water-mediated hydrogen-bond network
in the “NPxxY” motif, which is essential for mediating
the activation of the receptor. We thereby propose a hypothesis of
the water-mediated rhodopsin activation pathway.