Scrambling of disulfide bond scaffolds in neurotoxin AuIB: A molecular dynamics simulation study
Scrambling of disulfide bond scaffolds in neurotoxin AuIB: A molecular dynamics simulation study
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DOI：
10.1002/bip.22799
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发表时间：
2016-03-01
期刊：
影响因子：
2.9
通讯作者：
Lakshminarayanan, Madhavkrishnan
中科院分区：
文献类型：
--
作者：
Roy, Durba;Lakshminarayanan, Madhavkrishnan
AuIB是一种神经毒性螺螺肽，是人脑中烟碱型乙酰胆碱受体3-4亚型的选择性拮抗剂，因其在治疗疼痛方面的巨大潜力而被广泛研究。它含有两个二硫键，这两个键对维持其结构和功能选择性具有决定性作用。本文报道了水中二硫键对AuIB二级结构影响的分子动力学模拟研究。天然形式的AuIB(N)在水中非常稳定，具有非常健壮的3(10)和-螺旋结构域，约占总结构的47%。部分还原的AuIB(P2-8)，半胱氨酸2，8之间的二硫键断裂，显示出明显的扰动二级结构特征，螺旋度几乎完全丧失。另一方面，半胱氨酸3，15(P3-15)之间二硫键的断裂对多肽的螺旋区域几乎没有影响，尽管转角的重量增加了，但代价是随机卷曲。有趣的是，当两个二硫键都被破坏(D)时，螺旋区受到影响，但螺旋度的损失比在P2-8情况下观察到的要小。为了了解二硫键的扰乱过程，根据AuIB(D)中存在的四个半胱氨酸残基的硫-硫(SS)距离分布，估计了水中形成AuIB的三个二硫键异构体的相对概率。模拟结果表明，天然球状结构约占异构体总数的73%，其次是珠状结构。(C)2015 Wiley期刊，Inc.生物聚合物(Pept Sci)106：196-209,2016。
AuIB, a neurotoxic conopeptide, is a selective antagonist of the 3-4 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(10) and -helical domains, featuring approximate to 47% of the total structure. The partially reduced AuIB (P2-8), 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 (P3-15), on the other hand, has almost no effect on the helical region of the peptide, although the weightage of -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 P2-8 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 (SS) distance distributions of the four cysteine residues present in AuIB (D). Simulations show that the native globular form dominates approximate to 73% of the isoform population, with the beads form being the second most populated one. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 196-209, 2016.