Optimal Interstrand Bridges for Collagen-like Biomaterials

[Image: see text] In some natural collagen triple helices, cysteine (Cys) residues on neighboring strands are linked by disulfide bonds, enhancing association and maintaining proper register. Similarly, Cys–Cys disulfide bridges have been used to impose specific associations between collagen-mimetic peptides (CMPs). Screening a library of disulfide linkers in silico for compatibility with collagen identifies the disulfide bridge between proximal homocysteine (Hcy) and Cys as conferring much greater stability than a Cys–Cys bridge, but only when Hcy is installed in the Xaa position of the canonical Xaa–Yaa–Gly repeat and Cys is installed in the Yaa position. Experimental evaluation of CMPs that host alternative thiols validates this design: only Hcy-Cys bridges improve triple-helical structure and stability upon disulfide-bond formation. This privileged linker can enhance CMP-based biomaterials and enable previously inaccessible molecular designs.