Amyloid aggregation is a hallmark of many neurodegenerative and systemic diseases, where normally soluble proteins misassemble into fibrils. Recent advances in structural biology have revealed that amyloid fibrils often display structural polymorphism and undergo morphological evolution, yet existing amyloid models cannot describe these phenomena. Because the energy barrier between distinct fibril morphologies is high, direct interconversion is unlikely. Motivated by these observations, we propose a multi-pathway kinetic model in which nuclei of distinct sizes and stabilities give rise to different fibril morphologies. Our results demonstrate that the relative abundance and dynamics of polymorphic fibrils depend on the total initial protein concentration, nucleus size and stability, nucleus-fibril conformation conversion barrier, and morphology-dependent fibril stability. Importantly, nucleus size emerges as a key factor in concentration-dependent kinetics, exemplified by the non-canonical dependence of fibril-half time on protein concentration. Furthermore, nucleus-fibril conformation conversion barrier and morphology-dependent fibril stability govern hierarchical conversion from kinetically favored fibrils to thermodynamically more stable forms, consistent with experimentally observed time-dependent polymorphic evolution. Together, this work provides a unified kinetic framework that provides the mechanistic insights into how early nucleus heterogeneity drives fibril polymorphism and morphological evolution.
Bhandari et al. (Sun,) studied this question.