Division of Applied Mathematics , Brown University , Providence , Rhode Island 02912 , United States.
School of Engineering , Brown University , Providence , Rhode Island 02912 , United States.
J Phys Chem B. 2018 Dec 13;122(49):11302-11310. doi: 10.1021/acs.jpcb.8b07255. Epub 2018 Aug 27.
Accumulation and aggregation of amyloid are associated with the pathogenesis of many human diseases, such as Alzheimer's disease and Type 2 diabetes mellitus. Therefore, a quantitative understanding of the molecular mechanisms causing different aggregated structures and biomechanical properties of amyloid fibrils could shed some light into the progression of these diseases. In this work, we develop coarse-grained molecular dynamics (CGMD) models to simulate the dynamic self-assembly of two types of amyloids (amylin and amyloid β (Aβ)). We investigate the structural and mechanical properties of different types of aggregated amyloid fibrils. Our simulations demonstrate that amyloid fibrils could result from longitudinal growth of protofilament bundles, confirming one of the hypotheses on the fibril formation. In addition, we find that the persistence length of amylin fibrils increases concurrently with their pitch length, suggesting that the bending stiffness of amylin fibrils becomes larger when the amylin fibrils are less twisted. Similar results are observed for Aβ fibrils. These findings quantify the connection between the structural and the biomechanical properties of the fibrils. The CGMD models developed in this work can be potentially used to examine efficacy of anti-aggregation drugs, which could help in developing new treatments.
淀粉样蛋白的积累和聚集与许多人类疾病的发病机制有关，如阿尔茨海默病和 2 型糖尿病。因此，定量理解导致淀粉样纤维不同聚集结构和生物力学特性的分子机制，可以为这些疾病的进展提供一些启示。在这项工作中，我们开发了粗粒化分子动力学 (CGMD) 模型来模拟两种淀粉样蛋白（胰岛淀粉样多肽和淀粉样 β (Aβ)）的动态自组装。我们研究了不同类型聚集的淀粉样纤维的结构和力学特性。我们的模拟表明，淀粉样纤维可能是原纤维束纵向生长的结果，这证实了纤维形成的假说之一。此外，我们发现胰岛淀粉样多肽纤维的持久长度与其螺距长度同步增加，这表明当胰岛淀粉样多肽纤维的扭曲程度降低时，其弯曲刚度变大。Aβ 纤维也观察到类似的结果。这些发现定量地描述了纤维的结构和生物力学特性之间的联系。本工作中开发的 CGMD 模型可用于研究抗聚集药物的疗效，这有助于开发新的治疗方法。
