Molecular dynamics simulation on the inhibition mechanism of peptide-based inhibitor of islet amyloid polypeptide (IAPP) to islet amyloid polypeptide (IAPP(22-28)) oligomers
Molecular dynamics simulation on the inhibition mechanism of peptide-based inhibitor of islet amyloid polypeptide (IAPP) to islet amyloid polypeptide (IAPP(22-28)) oligomers
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肽类胰岛淀粉样多肽抑制剂(IAPP)对胰岛淀粉样多肽(IAPP(22-28))寡聚体抑制机制的分子动力学模拟
DOI：
10.1111/cbdd.12924
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发表时间：
2017
影响因子：
3
通讯作者：
Yao Xiaojun
中科院分区：
文献类型：
--
作者：
Zhou Shuangyan;Wang Qianqian;Ren Mengdan;Zhang Ai;Liu Huanxiang;Yao Xiaojun
胰岛淀粉样多肽(IAPP)的聚集与2型糖尿病的发生有关。Gly24和Ile26双N-甲基化修饰的NFGAIL具有可溶性、非淀粉样变性、无细胞毒性、抑制淀粉样蛋白形成和抑制IAPP的细胞毒性的特性。为了揭示这种多肽抑制剂的抑制机理，并为设计更多潜在的多肽抑制剂提供有用的信息，我们在显性溶剂中进行了分子动力学模拟。模拟结果表明，Gly24和Ile26在IAPP聚集过程中起着重要作用，这两个关键残基上的N-甲基化将破坏形成的低聚物的稳定性，阻止低聚物模板附近游离单体的构象转变。N-甲基化多肽抑制剂抑制IAPP聚集的原因是它能通过稳定的氢键作用与IAPP模板保持良好的结合。此外，它不能通过阻止自由单体与边界肽之间的氢键相互作用来诱导自由单体的构象转变。结构环境会在很大程度上影响游离单体在模板上的堆积。我们的研究从分子水平上揭示了多肽抑制剂的抑制机制，为今后设计和发现新的多肽抑制剂提供了指导。
Aggregation of islet amyloid polypeptide (IAPP) is implicated in the development of type 2 diabetes. The modified NFGAIL with doubleN‐methylated at Gly24 and Ile26 has the property of soluble, non‐amyloidogenic, non‐cytotoxic, and the ability of inhibiting amyloid formation and cytotoxicity of IAPP. To discover the inhibition mechanism of this peptide inhibitor and provide useful information to design more potential peptide inhibitors, molecular dynamics simulations in explicit solvent were performed. The simulation results reveal that Gly24 and Ile26 are of importance in IAPP aggregation, and N‐methylation at these two key residues will disrupt the stability of formed oligomer and prevent the conformation transition of free monomer near the oligomer template. The origin of the N‐methylated peptide inhibitor inhibiting IAPP aggregation is that it can keep good binding with IAPP template by stable hydrogen bonding interaction. Furthermore, it cannot induce the conformational transition of free monomer by preventing the hydrogen bond interaction between free monomer and boundary peptide. The structural environment can largely affect the stacking of free monomers to the template. Our study sheds light on the inhibition mechanism of peptide inhibitor at molecular level and may provide guidance for the future design and discovery of new peptide inhibitors.