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

1
Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA 01609, USA
2
Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA
3
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA
4
Schrödinger Inc., New York, NY 10036, USA
5
Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this manuscript.
Appl. Sci. 2019, 9(13), 2674; https://doi.org/10.3390/app9132674
Received: 28 April 2019 / Revised: 3 June 2019 / Accepted: 26 June 2019 / Published: 30 June 2019
(This article belongs to the Special Issue The Advances and Applications of Optogenetics)
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Abstract

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. View Full-Text
Keywords: Chlamydomonas reinhardtii; ion channel; optogenetics; electrophysiology; molecular dynamics simulations; membrane-protein interaction; energy of membrane deformation; CTMD method, residual hydrophobic mismatch Chlamydomonas reinhardtii; ion channel; optogenetics; electrophysiology; molecular dynamics simulations; membrane-protein interaction; energy of membrane deformation; CTMD method, residual hydrophobic mismatch
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Richards, R.; Mondal, S.; Weinstein, H.; Dempski, R.E. Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment. Appl. Sci. 2019, 9, 2674.

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