Synthesis, redox properties, and conformational analysis of vicinal disulfide ring mimics

Abstract

A vicinal disulfide ring (VDR) results from disulfide bond formation between two adjacent cysteine residues. This 8-membered ring is a rare motif in protein structures and is functionally important to those few proteins that posses it. This article focuses on the construction of strained and unstrained VDR mimics, discernment of the preferred conformation of these mimics, and the determination of their respective disulfide redox potentials.

Evidence for an Extended Hydrogen Bond Network in the Binding Site of the Nicotinic Receptor

“…When compared with the natural backbone (an amide), which favors the cis by 3.4 kcal/mol, the ester favors the trans by 1.4 kcal/mol. N-Methylation increases the cis preference of the parent (the amide backbone) to 9.3 kcal/mol, consistent with experimental studies on a similar system reported by Hondal and co-workers (22).…”

“…This is not a large energy difference, and indeed, both cis and trans forms have been seen in crystal structures of molecules that contain a vicinal disulfide (38,39). As such, it is reasonable to consider that perhaps cis-trans isomerization of the Cys-192-Cys-193 backbone may play a role in gating of nAChRs (10,18,19,21,22). This structural change could then easily be imagined to propagate along the protein backbone and perhaps initiate the "conformational wave" (40) that leads to gating.…”

“…Instead, many workers have speculated on a role in receptor gating involving cis-trans isomerization of the amide and/or gauche(ϩ)/gauche(Ϫ) interconversion of the disulfide (10,18,19,21,22). Conventional mutagenesis studies are expected to produce severely impaired receptors, and so it has been challenging to design unambiguous probes of disulfide function.…”

Redox active motifs in selenoproteins

“…The experimental 375-ppm resonance was either the cis-amide conformation 1 CA , 1 CAB , or 1 TTB . Previous conformational analysis of oxidized CC rings in peptides has suggested conformations with a cis-amide (11,29). In contrast, analysis of CC motifs in the PDB concluded that the occurrence of the cis conformation was remarkably low (30).…”

“…The size of the ring is directly linked to its chemical reactivity because if the strain is increased, the selenenylsulfide bond is destabilized. This in turn leads to a higher redox potential (more oxidizing), which favors a reduced protein (11,12). The 14-membered ring is the most ubiquitous motif in the selenoproteome.…”