Multiphoton Absorption Spectra of Channelrhodopsin-2 via Multiscale Simulation Methods.

Area of Science:

• Optogenetics and biophysics
• Computational chemistry and molecular modeling

Background:

• Channelrhodopsin-2 (ChR2) is crucial for optogenetics, enabling neuronal control via light.
• Its retinal Schiff base (RSB) undergoes isomerization upon light absorption.
• Limited light penetration in tissues necessitates multiphoton absorption (MPA) techniques for optogenetics.

Purpose of the Study:

• To develop and validate a fully atomistic multiscale methodology for computing ChR2's one-, two-, and three-photon absorption spectra.
• To investigate the impact of different molecular dynamics simulations on MPA spectra.
• To provide theoretical MPA spectra for ChR2, advancing optogenetic applications.

Main Methods:

• Integration of molecular mechanics (MM), molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM)-MD, and polarizable embedding (PE).
• Derivation of environment-specific PE potentials from explicit protein-lipid-solvent systems.
• Computation of spectra using PE-time-dependent density functional theory (PE-TD-DFT).

Main Results:

• Validated the methodology against experimental one-photon absorption spectra of ChR2.
• Reported the first theoretical two- and three-photon absorption spectra for ChR2.
• Observed spectral differences attributed to structural variations between classical MD and QM/MM-MD sampling of RSB moieties.

Conclusions:

• The developed multiscale methodology accurately predicts ChR2 absorption spectra.
• This work provides crucial theoretical insights into ChR2's multiphoton absorption properties.
• The findings support the advancement of MPA-based optogenetic strategies.