Disulfide bridges: bringing together frustrated structure in a bioactive peptide

Zhang, Yi, Schulten, Klaus, Gruebele, Martin, Bansal, Paramjit S., Wilson, David T., and Daly, Norelle L. (2016) Disulfide bridges: bringing together frustrated structure in a bioactive peptide. Biophysical Journal, 110 (8). pp. 1744-1752.

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Abstract

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 (Cys¹¹-Cys²³ and Cys¹⁷-Cys²⁹) are anticorrelated within ∼1 μs 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 Cys⁴-Cys²¹ 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 Cys⁴-Cys²¹ bridge deleted can still fold into its near-native structure even in its noncyclic form, confirming the lesser role of the Cys⁴-Cys²¹ 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.

Item ID: 44085
Item Type: Article (Research - C1)
ISSN: 1542-0086
Funders: Australian Research Council (ARC), National Institutes of Health (NIH), Pittsburgh Supercomputing Center (PSC)
Projects and Grants: NIH grant 9P41GM104601, NIH grant 2R01-GM093318, NIH/PSC grant PSCA15066P
Date Deposited: 12 Aug 2016 02:06
FoR Codes: 03 CHEMICAL SCIENCES > 0304 Medicinal and Biomolecular Chemistry > 030406 Proteins and Peptides @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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