Scrambling of disulfide bond scaffolds in neurotoxin AuIB: A molecular dynamics simulation study.

AuIB, a neurotoxic conopeptide, is a "selective antagonist" of the α3-β4 subtype of the nicotinic acetylcholine receptors in human brain and is investigated extensively for its immense potency in the treatment of pain. It contains two disulfide linkages, which are decisive in maintaining its structure and functional selectivity. Here we report, a molecular dynamics simulation study of the role of disulfide bonds on the secondary structure of AuIB in water. The native form of AuIB (N) is found to be significantly stable in water with very robust 3 and α-helical domains, featuring ∼47% of the total structure. The partially reduced AuIB (P ), with the disulfide bond between cysteine 2, 8 broken, shows significantly perturbed secondary structural features with almost total loss in helicity. Breaking of the disulfide bond between cysteine 3, 15 (P ), on the other hand, has almost no effect on the helical region of the peptide, although the weightage of β-turn increased at the cost of random coil. Intriguingly, when both the disulfide bonds are broken (D), the helical region is affected, but the loss in helicity is less than that observed in the P case. To understand the disulfide scrambling process, the relative probabilities of forming three disulfide-bond isoforms of AuIB in water are estimated from the sulfur-sulfur (SS) distance distributions of the four cysteine residues present in AuIB (D). Simulations show that the native globular form dominates ∼73% of the isoform population, with the beads form being the second most populated one. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 196-209, 2016.