Abstract
Rapid growth of amyloid fibrils via seeded conformational conversion of monomers, is a critical step of fibrillization and important for the prion-like transmission of amyloid diseases. Amyloid fibrils are often polymorphic with relative populations morphology-dependent, but the molecular mechanisms of fibril elongation and corresponding morphological dependence remain poorly understood. Here, we applied replica exchange all-atom discrete molecular dynamics simulations to study the conformational conversion of hIAPP, an amyloid peptide associated with type-2 diabetes, catalyzed by two representative fibrils with distinct morphologies where hIAPP adopted S-shaped and extended conformations correspondingly. For both cases, the incorporation of monomers into the preformed fibrils with parallel in-register alignments was observed in our unbiased simulations. The fibril elongation free energy landscape derived from simulations is characterized by multiple basins corresponding to different intermediate states. Fibril morphology affected monomer binding at fibril elongation and lateral surfaces, and also the conformational conversion dynamics at the elongation surface, resulting into different elongation rates and thus relative populations for different fibril morphologies as observed experimentally. We also investigated the dynamics of hIAPP monomers bound to the fibril elongation surfaces at opposite ends. We observed distinct free energy landscapes in agreement with experimentally-observed asymmetric fibril growth, which can be attributed to subtle physicochemical difference of two ends in terms of contacting surfaces and patterns of available hydrogen bond donors and acceptors. Together, our results offered molecular insights to seeded conformational conformation of fibril elongation, morphological dependence, asymmetry fibril growth, and could shed light on amyloid strains with distinct disease progression.
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