n →π* Interactions Modulate the Properties of Cysteine Residues and Disulfide Bonds in Proteins
Author(s)
Kilgore, Henry R.; Raines, Ronald T![Thumbnail](/bitstream/handle/1721.1/125597/nihms-1017231.pdf.jpg?sequence=4&isAllowed=y)
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Noncovalent interactions are ubiquitous in biology, taking on roles that include stabilizing the conformation of and assembling biomolecules, and providing an optimal environment for enzymatic catalysis. Here, we describe a noncovalent interaction that engages the sulfur atoms of cysteine residues and disulfide bonds in proteins - their donation of electron density into an antibonding orbital of proximal amide carbonyl groups. This n→π∗ interaction tunes the reactivity of the CXXC motif, which is the critical feature of thioredoxin and other enzymes involved in redox homeostasis. In particular, an n→π∗ interaction lowers the pK a value of the N-terminal cysteine residue of the motif, which is the nucleophile that initiates catalysis. In addition, the interplay between disulfide n→π∗ interactions and C5 hydrogen bonds leads to hyperstable β-strands. Finally, n→π∗ interactions stabilize vicinal disulfide bonds, which are naturally diverse in function. These previously unappreciated n→π∗ interactions are strong and underlie the ability of cysteine residues and disulfide bonds to engage in the structure and function of proteins.
Date issued
2018-12Department
Massachusetts Institute of Technology. Department of ChemistryJournal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Kilgore, Henry R. and Ronald T. Raines. “n →π* Interactions Modulate the Properties of Cysteine Residues and Disulfide Bonds in Proteins.” Journal of the American Chemical Society 140 (2018): 17606-17611 © 2018 The Author(s)
Version: Author's final manuscript
ISSN
0002-7863