Cis-trans isomerization of peptoid residues in the collagen triple-helix

Rongmao Qiu, Xiaojing Li, Kui Huang, Weizhe Bai, Daoning Zhou, Gang Li (), Zhao Qin () and Yang Li ()
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Rongmao Qiu: the Fifth Affiliated Hospital, Sun Yat-sen University
Xiaojing Li: the Fifth Affiliated Hospital, Sun Yat-sen University
Kui Huang: the Fifth Affiliated Hospital, Sun Yat-sen University
Weizhe Bai: the Fifth Affiliated Hospital, Sun Yat-sen University
Daoning Zhou: the Fifth Affiliated Hospital, Sun Yat-sen University
Gang Li: the Fifth Affiliated Hospital, Sun Yat-sen University
Zhao Qin: Syracuse University
Yang Li: the Fifth Affiliated Hospital, Sun Yat-sen University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Cis-peptide bonds are rare in proteins, and building blocks less favorable to the trans-conformer have been considered destabilizing. Although proline tolerates the cis-conformer modestly among all amino acids, for collagen, the most prevalent proline-abundant protein, all peptide bonds must be trans to form its hallmark triple-helix structure. Here, using host-guest collagen mimetic peptides (CMPs), we discover that surprisingly, even the cis-enforcing peptoid residues (N-substituted glycines) form stable triple-helices. Our interrogations establish that these peptoid residues entropically stabilize the triple-helix by pre-organizing individual peptides into a polyproline-II helix. Moreover, noting that the cis-demanding peptoid residues drastically reduce the folding rate, we design a CMP whose triple-helix formation can be controlled by peptoid cis-trans isomerization, enabling direct targeting of fibrotic remodeling in myocardial infarction in vivo. These findings elucidate the principles of peptoid cis-trans isomerization in protein folding and showcase the exploitation of cis-amide-favoring residues in building programmable and functional peptidomimetics.

Date: 2023
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DOI: 10.1038/s41467-023-43469-8

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