Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 140, Issue 50, Pages 17606-17611Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.8b09701
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Funding
- NIH [R01 GM044783, S10 OD023532]
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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 ->pi* 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 ->pi* 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 ->pi* interactions and C5 hydrogen bonds leads to hyperstable beta-strands. Finally, n ->pi* interactions stabilize vicinal disulfide bonds, which are naturally diverse in function. These previously unappreciated n ->pi* interactions are strong and underlie the ability of cysteine residues and disulfide bonds to engage in the structure and function of proteins.
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