(169cf) Molecular Dynamics Simulation Study of the Huntingtin Fibril’s Morphology, Stability, Kinetics, and Role of Water

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.