Modular Photoswitchable Molecular Glues for Chemo‐Optogenetic Control of Protein Function in Living Cells

Optogenetic systems using photosensitive proteins and chemically induced dimerization/proximity (CID/CIP) approaches enabled by chemical dimerizers (also termed molecular glues), are powerful tools to elucidate the dynamics of biological systems and to dissect complex biological regulatory networks. Here, we report a versatile chemo-optogenetic system using modular, photoswitchable molecular glues (sMGs) that can undergo repeated cycles of optical control to switch protein function on and off. We use molecular dynamics (MD) simulations to rationally design the sMGs and further expand their scope by incorporating different photoswitches, resulting in sMGs with customizable properties. We demonstrate that this system can be used to reversibly control protein localization, organelle positioning, protein-fragment complementation as well as posttranslational protein levels by light with high spatiotemporal precision. This system enables sophisticated optical manipulation of cellular processes and thus opens up a new avenue for chemo-optogenetics.