Photoswitchable Lipids for the Optical Control of Mechanosensitive Ion Channels

传统意义上的光遗传学，即使用从天然丰富的发色团（视网膜、黄素等）获得其光敏感性的工程蛋白，只是用光影响生物活动的一种方式。另一种选择是由Photopharmacology提供的，我们将其定义为用合成光开关控制生物活性的努力。这些可以共价或非共价连接到目的蛋白质上。然而，光开关也可以整合到脂质中，通过蛋白质/脂质相互作用直接影响跨膜蛋白，或通过改变宿主蛋白质的膜的结构和动力学间接影响跨膜蛋白。这将很难用纯粹的遗传方法编码。观察到的机械敏感通道，在响应于脂质双层的侧压力的变化打开和关闭的脂质和蛋白质之间的一个特别密切的耦合。为了更好地理解蛋白质和脂质膜之间的耦合的一般原理，并影响这一过程与光，我们建议使用一个相结合的实验/理论方法，依赖于光开关脂质（光脂）。这些光脂来源于膜的天然组分，并且可通过化学合成获得。关于通道，我们将研究MscL，这是一种机械敏感通道的细菌模型系统，以及哺乳动物TRAAK钾通道。实验和模拟将使我们了解光脂如何改变膜的结构和动力学，并推导出脂质/蛋白质耦合的分子图像。这项工作将进一步指导设计和合成功能改进的光脂的方法。最终，我们的光脂可能使机械敏感通道的光学控制成为听觉和触觉和疼痛感知的基础。

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.