Departamento de Física, FFCLRP, Universidade de São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, 14040-901, SP, Brazil.
Departamento de Química, FFCLRP, Universidade de São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, 14040-901, SP, Brazil.
J Mol Model. 2019 Aug 19;25(9):263. doi: 10.1007/s00894-019-4137-x.
The USFDA has approved pramlintide, commercially named Symlin (sIAPP), as adjunctive therapy for type 2 diabetes (T2D). This analogue of the human amylin peptide (hIAPP) has triple proline substitutions typical of the rat isoform (rIAPP). Recently, it was proposed that pramlintide solubility and aggregation resistance might be improved by incorporating further mutations, as S20R, screened from the wild-type porcine isoform (pIAPP), which leads to the variant named sIAPP. To better elucidate how such properties might be systematically induced in rationally designed analogues, we performed comparative assessments of rIAPP, sIAPP, and sIAPP using replica-exchange molecular dynamics (REMD) with an accurate combination of force field Charmm22* and explicit aqueous solvation TIP4P/Ew. Our thermo-structural analyses show that sIAPP exhibits a thermal conversion channel of helices[Formula: see text]-sheets resembling hIAPP. This channel is depleted in rIAPP and is absent in sIAPP. As a consequence, sIAPP presents an overall decrease of β-like secondary structures and an overstabilization of α-helices. Additionally, we observed in rIAPP and sIAPP an increase in the backbone RMSF of molecular terminals and the exposed area of key residues. These structural features of sIAPP suggest a nonamyloidogenic character, which is corroborated by our judicious estimate of the electrostatic component of the solvation free energy using a generalized Born model, and so it may constitute an alternative strategy to sIAPP as a peptide analogue of hIAPP. Furthermore, our findings confirm that different aggregation propensities of amylin and its analogues are synergistically modulated by long-range effects of key mutations. Graphical Abstract S20R-Pramlintide.
美国食品和药物管理局（FDA）已批准普兰林肽（Symlin，sIAPP）作为 2 型糖尿病（T2D）的辅助治疗药物。这种人胰岛淀粉样多肽（hIAPP）类似物具有典型的大鼠同工型（rIAPP）的三个脯氨酸取代。最近，有人提出通过进一步突变来提高普兰林肽的溶解度和抗聚集性，例如从野生型猪同工型（pIAPP）筛选出的 S20R，从而得到命名为 sIAPP 的变体。为了更好地阐明如何通过合理设计的类似物系统地诱导这些特性，我们使用Replica-Exchange 分子动力学（REMD）进行了 rIAPP、sIAPP 和 sIAPP 的比较评估，该方法使用了准确的 Charmm22*力场和显式水性溶剂 TIP4P/Ew 的组合。我们的热结构分析表明，sIAPP 表现出类似于 hIAPP 的热转换通道，由螺旋[Formula: see text]-片组成。该通道在 rIAPP 中被耗尽，在 sIAPP 中不存在。因此，sIAPP 表现出整体β-样二级结构减少和α-螺旋过度稳定。此外，我们在 rIAPP 和 sIAPP 中观察到分子末端的骨架 RMSF 和关键残基暴露面积增加。sIAPP 的这些结构特征表明其具有非淀粉样特性，这得到了我们使用广义 Born 模型对溶剂化自由能的静电分量进行明智估计的支持，因此它可能是 hIAPP 肽类似物的替代策略。此外，我们的研究结果证实，淀粉样肽及其类似物的不同聚集倾向是通过关键突变的远程效应协同调节的。
