TCB Publications - Abstract

TCB Publications - Abstract

Yi Zhang, Klaus Schulten, Martin Gruebele, Paramjit S. Bansal, David Wilson, and Norelle L. Daly. Disulfide bridges: bringing together frustrated structure in a bioactive peptide. Biophysical Journal, 110:1744-1752, 2016. (PMC: PMC4850350)

ZHAN2016A Disulfide bridges are commonly found covalent bonds that are usually believed to maintain structural stability of proteins. Here, we investigate the influence of disulfide bridges on protein dynamics through molecular dynamics simulations on the cysteine-rich trypsin inhibitor MCoTI-II with three disulfide bridges. Correlation analysis of the reduced cyclic peptide shows that two of the three disulfide distances (Cys$^{11}$-Cys$^{23}$ and Cys$^{17}$-Cys$^{29}$) are anticorrelated within $\sim$1 $\mu$s of bridge formation or dissolution: when the peptide is in nativelike structures and one of the distances shortens to allow bond formation, the other tends to lengthen. Simulations over longer timescales, when the denatured state is less structured, do not show the anticorrelation. We propose that the native state contains structural elements that frustrate one another’s folding, and that the two bridges are critical for snapping the frustrated native structure into place. In contrast, the Cys$^4$-Cys$^{21}$ bridge is predicted to form together with either of the other two bridges. Indeed, experimental chromatography and nuclear magnetic resonance data show that an engineered peptide with the Cys$^4$-Cys$^{21}$ bridge deleted can still fold into its near-native structure even in its noncyclic form, confirming the lesser role of the Cys$^4$-Cys$^{21}$ bridge. The results highlight the importance of disulfide bridges in a small bioactive peptide to bring together frustrated structure in addition to maintaining protein structural stability.

Download Full Text

The manuscripts available on our site are provided for your personal use only and may not be retransmitted or redistributed without written permissions from the paper's publisher and author. You may not upload any of this site's material to any public server, on-line service, network, or bulletin board without prior written permission from the publisher and author. You may not make copies for any commercial purpose. Reproduction or storage of materials retrieved from this web site is subject to the U.S. Copyright Act of 1976, Title 17 U.S.C.

Download full text: Request a Copy, Journal