Atomistic islet amyloid polypeptide fibril simulations reveal interplay of amyloid kinetic and mechanical stability

Abstract The aggregation of human islet amyloid polypeptide (IAPP) into amyloid fibrils triggers the degeneration of pancreatic β -cells and is a hallmark of type 2 diabetes. We introduce a molecular dynamics (MD) framework for simulating infinite amyloid fibrils by seamlessly and periodically repeating a finite fibril unit. The fibril Young’s modulus obtained from our MD simulations is close to experimental measurements, indicating that the mechanical properties of our model align with bulk experimental samples. Utilizing enhanced-sampling MD simulations and kinetic modeling that accounts for non-Markovian friction, we reveal that the thermal breaking time of a 10 μ m fibril decreases from ≈ 10 34 years in the absence of an external force to ≈ 1 ms under tensile loading of 2.6 nN. Our results demonstrate the intimate coupling between hydrogen bonding, amyloid mechanical and kinetic stability, and thereby enable new avenues for investigating the stability of amyloid fibrils and offer a framework for the rational design of therapeutics aimed at promoting fibril disassembly.