Understanding the Twisted Structure of Amyloid Fibrils via Molecular Simulations
mediaposted on 14.08.2018, 00:00 by Lu Lu, Yixiang Deng, Xuejin Li, He Li, George Em Karniadakis
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.