Abstract
Channelrhodopsins are light-sensitive ion channels whose reaction cycles involve conformation-coupled transfer of protons. Understanding how channelrhodopsins work is important for applications in optogenetics, where light activation of these proteins triggers changes in the transmembrane potential across excitable membranes. A fundamental open question is how the protein environment ensures that unproductive proton transfer from the retinal Schiff base to the nearby carboxylate counterion is avoided in the resting state of the channel. To address this question, we performed combined quantum mechanical/molecular mechanical proton transfer calculations with explicit treatment of the surrounding lipid membrane. The free energy profiles computed for proton transfer to the counterion, either via a direct jump or mediated by a water molecule, demonstrate that, when retinal is all-trans, water and protein electrostatic interactions largely favour the protonated retinal Schiff base state. We identified a conserved lysine group as an essential structural element for the proton transfer energetics in channelrhodopsins.
Highlights
Channelrhodopsins are light-sensitive ion channels whose reaction cycles involve conformation-coupled transfer of protons
To characterize the energetics of proton transfer in all-trans ChR1 and helices F–G of ChR2 (C1C2), we pursued an exhaustive set of quantum mechanical/molecular mechanical (QM/MM) computations, in which we studied the dynamics and calculated proton transfer pathways for conformations of wild-type C1C2 that were representative for the active site dynamics observed
The occupancies of selected active site hydrogen bonds computed for these quantum mechanics (QM)/MM simulations were mostly higher than in the corresponding MM simulations (Tables 3 and 4). We suggest that these differences in the occupancies of selected hydrogen bonds in MM vs QM/MM simulations are likely due to the fact that the QM/MM simulations, whose length is limited by the computational costs, provide an incomplete picture of the dynamics of the complex hydrogen-bonding network of C1C2
Summary
Channelrhodopsins are light-sensitive ion channels whose reaction cycles involve conformation-coupled transfer of protons. Understanding how channelrhodopsins work is important for applications in optogenetics, where light activation of these proteins triggers changes in the transmembrane potential across excitable membranes. A fundamental open question is how the protein environment ensures that unproductive proton transfer from the retinal Schiff base to the nearby carboxylate counterion is avoided in the resting state of the channel. To address this question, we performed combined quantum mechanical/molecular mechanical proton transfer calculations with explicit treatment of the surrounding lipid membrane. We identified a conserved lysine group as an essential structural element for the proton transfer energetics in channelrhodopsins
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