AbstractPhoto‐controlled affinity reagents seek to provide modular spatiotemporal control of bioactivity by conferring photo‐switchability of function on an affinity reagent scaffold. Herein we used Rosetta‐based computational methods to screen for sites on the Fynomer affinity reagent structure for attachment of photoswitchable cross‐linkers. Both established UV‐based cross‐linkers (azobenzene‐iodoacetamide (IAC)) and an azonium‐based efficient red‐light‐switchable cross‐linker, piperazino‐tetra‐ortho‐methoxy azobenzene (PIP), were then tested experimentally. Several sites compatible with Fynomer function were identified, including sites showing rapid (<10 s) red light (633 nm) modulation of function. Although a range of overall target binding affinities were observed, the degree of photo‐switchability of Fynomer function was generally small (<twofold). Computational models suggest that local flexibility limits the degree of switching seen in these designs.