This review presents an overview on biohybrid approaches of integrating the structural and functional features of proteins and peptides with synthetic polymers and the resulting unique properties in such hybrids, with a focus on bioresponsive/bioactive systems with biomaterials applications. The review is divided in two broad sections. First, we describe several examples of biohybrids produced by combining versatile synthetic polymers with proteins/enzymes and drugs that have resulted in (1) hybrid materials based on responsive polymers, (2) responsive hydrogels based on enzyme-catalyzed reactions, protein–protein interactions and protein–drug sensing, and (3) dynamic hydrogels based on conformational changes of a protein. Next, we present hybrids produced by combining synthetic polymers with peptides, classified based on the properties of the peptide domain: (1) peptides with different conformations, such as α-helical, coiled-coil, and β-sheet; (2) peptides derived from structural protein domains such as silk, elastin, titin, and collagen; and (3) peptides with other biofunctional properties such as cell-binding domains and enzyme-recognized degradation domains.

The mechanical and biological functions of the native collagens remain an inspiration in materials design, but widespread application of de novo collagens has been limited in part by the need for hydroxylated proline in the formation of stable triple helical structures. In order to address this continued need and to expand the potential for recombinant expression of functional, hydroxyproline-lacking collagen-mimetic peptides, we have designed a hydrophilic, non-repetitive, and thermally stable collagen-mimetic peptide via the incorporation of triple-helix-stabilizing charged triplets. The peptide sequence is also equipped with a type III-collagen-mimetic cystine knot at the C-terminus to facilitate covalent crosslinking of the triple helix via simple air oxidation. Circular dichroic (CD) studies of this collagen-mimetic peptide revealed a typical, thermally stable, collagen triple helix signature, with a weak positive maximum at 225 nm, and a triple helix melting temperature (Tm) of 35 °C and 43 °C for the reduced and oxidized forms respectively. The thermal behavior was confirmed via analysis by differential scanning calorimetry. Interestingly, this hydroxyproline-lacking, collagen-mimetic peptide also assembles into nanorods and microfibrillar structures as observed via transmission electron microscopy. The identification and demonstrated useful collagen-mimetic properties of this peptide suggests important opportunities in the recombinant design of new collagen-based biomaterials.