The structure and function of conopeptides are usually strongly modulated by disulfide bond linkage patterns. Conopeptide AuIB is a selective inhibitor of the mammalian α₃β₄ nicotinic acetylcholine receptor (nAChR), found in the neuromuscular junctions. The non-native ribbon isoform of α-conotoxin, AuIB, is reported to be significantly more potent than the native globular isoform. However, experiments show that their binding sites on mammalian nAChR are different. The difference in the structure and dynamics of these two isoforms when bound to the globular isoform binding site in homology modeled human (α₃)₃-(β₄)₂ nAChR is explored in this work. The isoforms are compared in their unbound and bound states through equilibrium and replica exchange molecular dynamics simulations. Interaction energy map between the key peptide and the receptor residues involved in binding, secondary structures of the peptide and intra-peptide H-bonding patterns bring out the difference in non-bonding interactions and structure of the isoforms while being bound to the receptor. Dynamics exhibited by the isoforms as followed by principal component analysis (PCA), using internal coordinates of backbone dihedral angles, reveal that the ribbon isoform is significantly more flexible as compared to the globular isoform, when bound to the latter's binding site, near the Cys-loop of the α₃(+)β₄(−) junction of human (α₃)₃(β₄)₂ nAChR. The works brings out differences in the structure and dynamical modes exhibited by the isoforms as it explores the receptor surface.

中文翻译：

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人α3β4nAChR存在下conopeptide AuIB的二硫键同工型的差异结构和动力学的模拟

肽的结构和功能通常受二硫键连接模式的强烈调节。芋螺肽AuIB是哺乳动物的选择性抑制剂α ₃ β ₄烟碱乙酰胆碱受体（nAChR的），在神经肌肉接头处找到。据报道，α-芋螺毒素的非天然带状亚型AuIB比天然球形亚型的效力要强得多。但是，实验表明它们在哺乳动物nAChR上的结合位点是不同的。在该结构中，并且这两个同工型的动力学的差异时在同源性建模的人结合到球状同种型结合位点（α ₃）₃ - （β ₄）₂在这项工作中探讨了nAChR。通过平衡和复制交换分子动力学模拟比较同工型的未结合和结合状态。关键肽与参与结合的受体残基之间的相互作用能图，肽的二级结构和肽内H键结合模式在结合到受体上时揭示了非键相互作用和同工型结构的差异。通过使用骨架主二面角的内部坐标进行主成分分析（PCA）之后，同工型表现出的动力学结果表明，与球形同工型结合到球状同工型附近时，与球状同工型相比，带状同工型的柔性要大得多。 -loop所述的α ₃（+）β ₄（ - ）人的结（α ₃）₃（β ₄）₂的nAChR。这项工作揭示了同工型探索受体表面时在结构和动力学模式方面的差异。