Peptoid Residues Make Diverse, Hyperstable Collagen Triple-Helices
journal contributionposted on 2021-07-13, 20:08 authored by Julian L. Kessler, Grace Kang, Zhao Qin, Helen Kang, Frank G. Whitby, Thomas E. Cheatham, Christopher P. Hill, Yang Li, S. Michael Yu
As the only ribosomally encoded N-substituted amino acid, proline promotes distinct secondary protein structures. The high proline content in collagen, the most abundant protein in the human body, is crucial to forming its hallmark structure: the triple-helix. For over five decades, proline has been considered compulsory for synthetic designs aimed at recapitulating collagen’s structure and properties. Here we describe that N-substituted glycines (N-glys), also known as peptoid residues, exhibit a general triple-helical propensity similar to or greater than proline, enabling synthesis of stable triple-helical collagen mimetic peptides (CMPs) with unprecedented side chain diversity. Supported by atomic-resolution crystal structures as well as circular dichroism and computational characterizations spanning over 30 N-gly-containing CMPs, we discovered that N-glys stabilize the triple-helix primarily by sterically preorganizing individual chains into the polyproline-II helix. We demonstrated that N-glys with exotic side chains including a “click”-able alkyne and a photosensitive side chain enable CMPs for functional applications including the spatiotemporal control of cell adhesion and migration. The structural principles uncovered in this study open up opportunities for a new generation of collagen-mimetic therapeutics and materials.
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N-substituted glycinesproline contentHyperstable Collagen Triple-Helicessterically preorganizingside chain diversityside chain30 N-gly-containing CMPscell adhesionside chainstriple-helical propensitycollagen-mimetic therapeuticspolyproline-II helixpeptoid residueshallmark structuretriple-helical collagenatomic-resolution crystal structuresPeptoid Residuesprotein structurestriple-helixspatiotemporal control