Study of Ultra-Fast Rhodopsin Activation Dynamics with Molecular Dynamics Simulations

Abstract

Rhodopsin is a photo-sensitive membrane protein that, when excited by light, can activate the signaling pathway that leads to scotopic vision in mammals. Although this receptor is well-characterized, there is limited structural information about the events that occur immediately after light-excitation, as they take place in notably short time regimes (fs-ns) and they are not easily captured experimentally. These events comprise the cis-to-trans isomerization of the protein′s ligand after photon absorption, and a subsequent relaxation process that drives the receptor through a series of spectroscopically distinguishable intermediates. All-atom molecular dynamics simulations can be a powerful tool for the study of these ultra-fast dynamic events in silico and aid the interpretation of emerging experimental techniques, such as time-resolved small- and wide-angle X-ray scattering with free-electron lasers. The temporal resolution of simulations is only limited by storage space and, because the times of interest are quite short (fs-ps), it is feasible to run a large number of trajectories, improving the convergence of the results and facilitating the assessment of functionally relevant phenomena. Starting from well-equilibrated microsecond-scale dark-state rhodopsin simulations, we run and analyze 3,000 pairs of 100 ps trajectories in two conditions (dark and light-excited) to model the process of energy dispersion across the protein after light-excitation. Because these pairs of simulations start out with identical coordinates, cancellation of signals not related to photon absorption or retinal isomerization is expected to be optimal. Following this strategy, we observe a small, but statistically significant, increase in the radius of gyration of the receptor after light-excitation and a propagation of the light-induced perturbation across the protein that occurs at speeds close to those found for other light-reactive proteins, like myoglobin and bacteriorhodopsin.