Protein affinity reagents play an important role across a wide-range of life science applications. Efforts to enhance affinity reagents through protein engineering typically focus on improved affinity or stability. Here, we examine methods to engineer coupled equilibria that are linked to the protein binding event, which result in protein variants that can be regulated reversibly, based on environmental conditions. Using single domain (VHH) antibodies as model affinity reagents, along with combinatorial libraries, which provide a route to screen new and wild-type residues across a significant amount of interface surface area, we explore the creation of either pH- or metal ion-dependent protein recognition. The resulting protein variants have been analyzed to evaluate the structural and thermodynamic consequences of the remodeled interfaces on protein regulation and stability. The results suggest the ability to introduce new function, such as a reversible linked binding event, is likely to scale with the complexity/size of the protein-protein (ligand) interface. Furthermore, the combinatorial approach to introduce new function should be generally transferable to other protein affinity reagent scaffolds.