The channelrhodopsin 2 (ChR2) is a light-gated ion channel and a widely used tool in optogenetics. The photoisomerization of the retinal protonated Schiff base (RPSB) in ChR2 triggers the channel opening and firing of neuronal signals. Despite the importance of the ChR2, its light activation mechanism is still not fully understood in atomistic detail. In this work, we combine quantum dynamics, classical dynamics, electronic structure, and free energy calculations to comprehensively characterize the light activation mechanism of ChR2. Nonadiabatic dynamics simulations of both the wild type (WT) ChR2 and its E123T mutant are carried out using the <i>ab initio</i> multiple spawning (AIMS) method in a QM/MM setting, where spin-restricted ensemble-referenced Kohn-Sham (REKS) method is used to describe the QM region. Our simulations agree well with the experiments, and highlight the interplay between the photochemical reaction and the surrounding protein environment. (1) The E123T mutation changes the protein’s electrostatic environment around the RPSB, and significantly slows down its photoisomerization. (2) The photoisomerization facilitates its subsequent deprotonation and the hydration of the ion channel. This work presents the first simulation of the photodynamics of ChR2 with a correlated first-principles electronic structure method, and provides design principles for new optogenetic tools.

Light activation mechanism of channelrhodopsin 2

ACS Fall 2021

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