Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment

Richards, Ryan; Mondal, Sayan; Weinstein, Harel; Dempski, Robert E.

doi:10.3390/app9132674

Title: Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment

Journal Article · Sun Jun 30 00:00:00 EDT 2019 · Applied Sciences

DOI:https://doi.org/10.3390/app9132674· OSTI ID:1530465

Richards, Ryan; Mondal, Sayan;

; Dempski, Robert E.

Channelrhodopsin-2 (ChR2) is a light-gated ion channel that conducts cations of multiple valencies down the electrochemical gradient. This light-gated property has made ChR2 a popular tool in the field of optogenetics, allowing for the spatial and temporal control of excitable cells with light. A central aspect of protein function is the interaction with the surrounding lipid environment. To further explore these membrane-protein interactions, we demonstrate the role of residual hydrophobic mismatch (RHM) as a mechanistically important component of ChR2 function. We combined computational and functional experiments to understand how RHM between the lipid environment and ChR2 alters the structural and biophysical properties of the channel. Analysis of our results revealed significant RHM at the intracellular/lipid interface of ChR2 from a triad of residues. The resulting energy penalty is substantial and can be lowered via mutagenesis to evaluate the functional effects of this change in lipid-protein interaction energy. The experimental measurement of channel stability, conductance and selectivity resulting from the reduction of the RHM energy penalty showed changes in progressive H+ permeability, kinetics and open-state stability, suggesting how the modulation of ChR2 by the surrounding lipid membrane can play an important biological role and contribute to the design of targeted optogenetic constructs for specific cell types.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02- 05CH11231

OSTI ID:: 1530465

Journal Information:: Applied Sciences, Journal Name: Applied Sciences Vol. 9 Journal Issue: 13; ISSN 2076-3417

Publisher:: MDPI AGCopyright Statement

Country of Publication:: Switzerland

Language:: English

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Cited by: 1 work

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