Amide Rotation Hindrance Predicts Proteolytic Resistance of Cystine-Knot Peptides

Yanzi Zhou, Daiqian Xie, Yingkai Zhang

Research output: Contribution to journalArticlepeer-review


Cystine-knot peptides have remarkable stability against protease degradation and are attractive scaffolds for peptide-based therapeutic and diagnostic agents. In this work, by studying the hydrolysis reaction of a cystine-knot inhibitor MCTI-A and its variants with ab initio QM/MM molecular dynamics simulations, we have elucidated an amide rotation hindrance mechanism for proteolysis resistance: The proteolysis of MCTI-A is retarded due to the higher free energy cost during the rotation of NH group around scissile peptide bond at the tetrahedral intermediate of acylation, and covalent constraint provided by disulfide bonds is the key factor to hinder this rotation. A nearly linear correlation has been revealed between free energy barriers of the peptide hydrolysis reaction and the amide rotation free energy changes at the protease-peptide Michaelis complex state. This suggests that amide rotation hindrance could be one useful feature to estimate peptide proteolysis stability.

Original languageEnglish (US)
Pages (from-to)1138-1142
Number of pages5
JournalJournal of Physical Chemistry Letters
Issue number7
StatePublished - Apr 21 2016

ASJC Scopus subject areas

  • General Materials Science
  • Physical and Theoretical Chemistry


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