Amide Rotation Hindrance Predicts Proteolytic Resistance of Cystine-Knot Peptides.

ABSTRACT: 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 ro

SUBMITTER: Zhou Y 

PROVIDER: S-EPMC4824663 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature