ENLIGHT · Elucidating the Microscopic Origins of the Light-Induced Gating Mechanism in Channelrhodopsin-2

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Project objective

Alzheimer's disease is the most common form of dementia. It affects millions of people and is expected to increase in the coming decades due to aging of the population. Optogenetics combines optics and genetics to gain insight into brain function by genetically inserting light-sensitive transmembrane proteins into neurons. Channelrhodopsin-2 (ChR2) is an ion channel protein that enables precise temporal control turning neurons on or off in response to light. In vivo optogenetic experiments have a number of complications. One such complication is related to the wavelength of the visible light needed to activate ChR2. This results in high scattering by biological tissue as well as competition with hemoglobin which absorbs at a similar wavelength. Activation by multi-photon absorption processes (i.e., simultaneous absorption of multiple photons of longer wavelength) has the potential to mitigate both effects. Another complication is that ChR2 becomes inactive after prolonged illumination. This is related to its intricate photocycle. Gaining a detailed understanding of the molecular mechanism of the complete photocycle is crucial for solving these complications. To this end, ENLIGHT will use a holistic approach that combines multiscale quantum-classical methods, molecular dynamics simulations, and statistical analysis to obtain atomistic insight into the photoactivation, kinetics, and thermodynamics of the ChR2 photocycle. The acquired fundamental understanding of ChR2 will thus enable the development of next-generation optogenetic tools that have the potential to help us better understand the brain and neurodegenerative diseases. Dr. David Carrasco de Busturia (DCB) will carry out this project supervised by Prof. Patrick Norman at KTH, and a secondment at EPFL with Prof. Ursula Röthlisberger. This project, and the training provided, will be pivotal in advancing DCB's career goal of becoming a leading, innovative, and independent researcher in theoretical chemistry.

Original text from CORDIS.

Participants

• KUNGLIGA TEKNISKA HOEGSKOLAN · StockholmCoordinatorSweden
• ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE · LausanneSwitzerland

Links

• View on CORDIS
• DOI: 10.3030/101199012