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

Controlling the activation of the innate immune response, particularly through the use of suitable visible light sources, could pave the way for the development of innovative phototimmunotherapeutic strategies. In this contribution, we investigate the effects of the E/Z isomerization on a phosphatidylserine 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]. Specifically, we examine how this isomerization affects interactions with the innate immune system’s TIM-3 receptors. Using long-range molecular dynamics simulations with enhanced sampling, we demonstrate that the Z isomer leads to a shallower binding and a less pronounced rigidification of the protein compared to the E isomer and the native lipid, which explains the less pronounced activation of the immune response.