Dueling Backbones: Comparing Peptoid and Peptide Analogues of a Mussel Adhesive Protein

Ensembles of amino acid side chains often dominate the interfacial interactions of intrinsically disordered proteins; however, backbone contributions are far from negligible. Using a combination of nanoscale force measurements and molecular dynamics simulations, we demonstrated with analogous mussel-mimetic adhesive peptides and peptoids both 34 residues long that highly divergent adhesive/cohesive outcomes can be achieved on mica surfaces by altering backbone chemistry only. The Phe, Tyr, and Dopa containing peptoid variants used in this study deposited as dehydrated and incompressible films that facilitated analysis of peptoid side chain contributions to adhesion and cohesion. For example, whereas Phe and Dopa peptoids exhibited similar cohesion, Dopa peptoids were ∼3 times more adhesive than Phe peptoids on mica. Compared with the peptides, Phe peptoid achieved only ∼20% of Phe containing peptide adhesion, but the Dopa peptoids were >2-fold more adhesive than the Dopa peptides. Cation−π interactions accounted for some but not all of the cohesive interactions. Our results were corroborated by molecular dynamics simulations and highlight the importance of backbone chemistry and the potential of peptoids or peptoid/peptide hybrids as wet adhesives and primers.