Photoswitchable Lipids for the Optical Control of Mechanosensitive Ion Channels

• Applicants: Professorin Dr. Ana Nicoleta Bondar, Ph.D.; Professor Dr. Joachim Heberle; Dr. Martin Sumser, since 3/2017
• Subject Area: Biophysics ; Biological and Biomimetic Chemistry
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 315318991

Optogenetics in the conventional sense, i.e. the use of engineered proteins that gain their light-sensitivity from naturally abundant chromophores (retinal, flavins etc.), is only one way to influence biological activity with light. An alternative is provided by Photopharmacology, which we define as an effort to control biological activity with synthetic photoswitches. These can be covalently or non-covalently attached to the protein of interest. However, photoswitches can also be integrated into lipids that influence transmembrane proteins directly via protein/lipid interactions, or indirectly by altering the structure and dynamics of the membrane that hosts the protein. This would be difficult to encode with purely genetic methods. A particularly intimate coupling between lipids and proteins is observed for mechanosensitive channels, which open and close in response to changes in the lateral pressure of the lipid bilayer. To better understand general principles of coupling between proteins and lipid membranes and to influence this process with light, we propose to use a combined experimental/theoretical approach that relies on photoswitchable lipids (photolipids). These photolipids are derived from natural components of the membrane and are accessible trough chemical synthesis. With respect to the channels, we will investigate MscL, which is a bacterial model system for mechanosensitive channels, and the mammalian TRAAK potassium channel. Experiments and simulations will allow us to understand how photolipids alter the structure and dynamics of the membrane, and to derive a molecular picture of the lipid/protein coupling. This work will then guide further approaches towards the design and synthesis of functionally improved photolipids. Ultimately, our photolipids may enable the optical control of mechanosensitive channels that underlie hearing and the perception of touch and pain.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1926: Next Generation Optogenetics: Tool Development and Application
• Ehemaliger Antragsteller: Professor Dr. Dirk Trauner, until 2/2017