Unraveling the Role of Azobenzene‐Based Photoswitchable Lipids in Controlling Innate Immune Response

The control of the activation of the innate immune response, notably by using suitable visible light sources, may lead the way to the development of phototimmunotherapeutic strategies. In this contribution we analyze the effects of the E/Z interconversion on a phosphatidyl serine lipid containing an isomerizable azobenzene moiety, which has recently been shown to regulate the activation of natural killer cells and the production of cytokines [J. Am. Chem. Soc. 2022, 144, 3863 - 3874]. In particular, we analyze the differential interactions of the innate immune system TIM-3 sensors. We show, resorting to long-range molecular dynamic simulations including enhanced sampling, that the Z isomer leads to a slight decrease of the binding free energy coupled with a less pronounced rigidification of the protein compared to the E isomer and the native lipid, justifying its less pronounced activation of the immune response.