Site-Selective Protein Modification: From Functionalized Proteins to Functional Biomaterials

Abstract

Summary Chemists, biologists, and material scientists alike have long sought to control protein presentation, orientation, and activity within biomaterials to dictate reaction catalysis, biological signaling, and cell-fate specification. Such control is most typically achieved through the installation of reactive chemical handles onto proteins that govern static or dynamic biomacromolecule-material associations. Though convenient, stochastic functionalization strategies often yield ill-defined protein samples with severely diminished activity. In contrast, site-selective methodologies permit the controlled installation of material-interacting handles onto fragile proteins while preserving native structure and function. Here, we review methods that afford chemical, regioselective, and site-specific modification of proteins, emphasizing those that have found utility in the creation of functional biomaterials. We discuss cutting-edge strategies involving small-molecule-based labeling, genetic engineering, and chemoenzymatic reactions that provide precise control over the extent and location of protein modification. We assess the progress and look to the future in exploiting these functional proteins to create next-generational biomaterials for tissue engineering, therapeutic, and fundamental biological applications.