Protein aggregation during aging is implicated in numerous incurable neurodegenerative diseases, wherein functional proteins transform into dysfunctional biological condensates or, in some cases, create pathological amyloid fibrils through a liquid-to-solid transition (LST). The repetition of glutamine residues has a tendency to form pathological amyloid fibrils and has been linked to Polyglutamine (PolyQ) diseases, such as spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy, Huntington's disease, and spinal-bulbar muscular atrophy. Despite ongoing research efforts, there has been only indirect experimental measurement of the structure of PolyQ fibrils, and a comprehensive understanding of the early and later stages of amyloid formation remains elusive. In our study, we employ a multiscale simulation framework to test two available fibril structures of PolyQ, i.e., 𝛽-arc and 𝛽-turn. Although the 𝛽-arc model shows stronger fibril contacts, the 𝛽-turn model exhibits a higher stability. This attribute is associated with the observed higher interaction of water molecules within the 𝛽-turn fibril core, producing a hydrogen bonding network. We further investigate the effects of temperature and concentration on the mechanisms of fibrillation and fibril morphology. Our findings uncover a high degree of heterogeneity in fibril morphology, with distinct morphologies associated with varying levels of toxicity, and reveal that the antiparallel 𝛽-turn model of the PolyQ fibril exhibits faster kinetics.
