Open AccessPeptoid Residues Make Diverse, Hyperstable Collagen Triple-Helices
Author(s) -
Julian Kessler,
Grace Kang,
Zhao Qin,
Helen H. Kang,
Frank G. Whitby,
Thomas E. Cheatham,
Christopher P. Hill,
Yang Li,
S. Michael Yu
Publication year - 2021
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.1c00708
Subject(s) - triple helix , polyproline helix , peptoid , chemistry , collagen helix , circular dichroism , proline , side chain , steric effects , helix (gastropod) , stereochemistry , peptide , amino acid , biochemistry , polymer , ecology , organic chemistry , snail , biology
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.