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

Abstract

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 which the innate immune system TIM-3 sensors. We show, resorting to long-range molecular dynamic simulations including enhanced sampling, that the Z isomer lead 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/605494v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@89c52eorg.highwire.dtl.DTLVardef@f08fe9org.highwire.dtl.DTLVardef@1780d8eorg.highwire.dtl.DTLVardef@c1f3b8_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOTOC GRAPHICC_FLOATNO C_FIG