Institute for Molecular Engineering, University of Chicago, Chicago, Illinois 60637, USA.
J Chem Phys. 2018 Jul 14;149(2):025101. doi: 10.1063/1.5033458.
Amyloid aggregates of human islet amyloid polypeptide (hIAPP or human amylin) have long been implicated in the development of type II diabetes. While hIAPP is known to aggregate into amyloid fibrils, it is the early-stage prefibrillar species that have been proposed to be cytotoxic. A detailed picture of the early-stage aggregation process and relevant intermediates would be valuable in the development of effective therapeutics. Here, we use atomistic molecular dynamics simulations with a combination of enhanced sampling methods to examine the formation of the hIAPP dimer in water. Bias-exchange metadynamics calculations reveal relative conformational stabilities of the hIAPP dimer. Finite temperature string method calculations identify pathways for dimer formation, along with relevant free energy barriers and intermediate structures. We show that the initial stages of dimerization involve crossing a substantial free energy barrier to form an intermediate structure exhibiting transient β-sheet character, before proceeding to form an entropically stabilized dimer structure.
人胰岛淀粉样多肽（hIAPP 或人胰岛淀粉样蛋白）的淀粉样聚集物长期以来一直与 2 型糖尿病的发展有关。虽然已知 hIAPP 会聚集形成淀粉样纤维，但被认为具有细胞毒性的是早期的原纤维样物种。对早期聚集过程和相关中间体的详细描述将有助于开发有效的治疗方法。在这里，我们使用原子分子动力学模拟与增强采样方法相结合，研究 hIAPP 二聚体在水中的形成。偏见交换元动力学计算揭示了 hIAPP 二聚体的相对构象稳定性。有限温度字符串方法计算确定了二聚体形成的途径，以及相关的自由能障碍和中间结构。我们表明，二聚化的初始阶段涉及跨越一个很大的自由能障碍，形成一个表现出瞬态 β-折叠特征的中间结构，然后再形成一个熵稳定的二聚体结构。
