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An Atomistic Model of a Precursor State of Light-Induced Channel Opening of Channelrhodopsin.

ABSTRACT: Channelrhodopsins (ChRs) are microbial light-gated ion channels with a retinal chromophore and are widely utilized in optogenetics to precisely control neuronal activity with light. Despite increasing understanding of their structures and photoactivation kinetics, the atomistic mechanism of light gating and ion conduction remains elusive. Here, we present an atomic structural model of a chimeric ChR in a precursor state of the channel opening determined by an accurate hybrid molecular simulation technique and a statistical theory of internal water distribution. The photoactivated structure features extensive tilt of the chromophore accompanied by redistribution of water molecules in its binding pocket, which is absent in previously known photoactivated structures of analogous photoreceptors, and widely agrees with structural and spectroscopic experimental evidence of ChRs. The atomistic model manifests a photoactivated ion-conduction pathway that is markedly different from a previously proposed one and successfully explains experimentally observed mutagenic effects on key channel properties.

SUBMITTER: Cheng C

PROVIDER: S-EPMC6170652 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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An Atomistic Model of a Precursor State of Light-Induced Channel Opening of Channelrhodopsin.

Cheng Cheng C Kamiya Motoshi M Takemoto Mizuki M Ishitani Ryuichiro R Nureki Osamu O Yoshida Norio N Hayashi Shigehiko S

Biophysical journal 20180827 7

Channelrhodopsins (ChRs) are microbial light-gated ion channels with a retinal chromophore and are widely utilized in optogenetics to precisely control neuronal activity with light. Despite increasing understanding of their structures and photoactivation kinetics, the atomistic mechanism of light gating and ion conduction remains elusive. Here, we present an atomic structural model of a chimeric ChR in a precursor state of the channel opening determined by an accurate hybrid molecular simulation ...[more]

PMID: 30236783

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Project description:Channelrhodospin-2 (ChR2), a light-sensitive ion channel, and its variants have emerged as new excitatory optogenetic tools not only in neuroscience, but also in other areas, including cardiac electrophysiology. An accurate quantitative model of ChR2 is necessary for in silico prediction of the response to optical stimulation in realistic tissue/organ settings. Such a model can guide the rational design of new ion channel functionality tailored to different cell types/tissues. Focusing on one of the most widely used ChR2 mutants (H134R) with enhanced current, we collected a comprehensive experimental data set of the response of this ion channel to different irradiances and voltages, and used these data to develop a model of ChR2 with empirically-derived voltage- and irradiance- dependence, where parameters were fine-tuned via simulated annealing optimization. This ChR2 model offers: 1) accurate inward rectification in the current-voltage response across irradiances; 2) empirically-derived voltage- and light-dependent kinetics (activation, deactivation and recovery from inactivation); and 3) accurate amplitude and morphology of the response across voltage and irradiance settings. Temperature-scaling factors (Q10) were derived and model kinetics was adjusted to physiological temperatures. Using optical action potential clamp, we experimentally validated model-predicted ChR2 behavior in guinea pig ventricular myocytes. The model was then incorporated in a variety of cardiac myocytes, including human ventricular, atrial and Purkinje cell models. We demonstrate the ability of ChR2 to trigger action potentials in human cardiomyocytes at relatively low light levels, as well as the differential response of these cells to light, with the Purkinje cells being most easily excitable and ventricular cells requiring the highest irradiance at all pulse durations. This new experimentally-validated ChR2 model will facilitate virtual experimentation in neural and cardiac optogenetics at the cell and organ level and provide guidance for the development of in vivo tools.

Dataset Information

An Atomistic Model of a Precursor State of Light-Induced Channel Opening of Channelrhodopsin.

Publications

An Atomistic Model of a Precursor State of Light-Induced Channel Opening of Channelrhodopsin.

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