Modelling peptide self-assembly within a partially disordered tau filament

Abstract Peptide self-assemblies are a natural template for designing bio-inspired functional materials given the extensive characterisation of neurodegenerative and non-disease biological amyloid protein assemblies advances in rational, modelling-led design. These bioinspired employ design rules obtained from known aggregation-prone peptides or de novo screening sequences most amenable to self-assemble nanostructures. Here, we exploit hybrid nature complex peptide with both ordered crystalline intrinsically disordered regions, namely, microtubule-binding domain (MBD) tau protein, probe physical driving forces self-assembly at molecular level. We model its native mutated states identify supramolecular packing stabilisation prefibrillar use atomic-resolution dynamics computer simulations, contact maps, hydrogen-bond networks free energy calculations MBD two familial mutants, P301L K280Δ, along control double mutant, + K280Δ as first step towards understanding their effects on oligomer stability fibrillar fold. Our results indicate that mutations destabilise pro-fibrillar hexamer by breaking contacts MBD, which helps explain mutation-induced toxicity levels more stable wild-type may be less prone crumbling, producing fewer toxic small oligomeric seeds. important finding is causing frontotemporal dementia show distinct morphologies delineating different stages self-assembly. The models mutant pro-nucleating low tendency assembly polymerisation, whereas pro-elongating potential protofibrillar growth. data provides predictive mechanistic features depending location single missense partially pathogenic prevalence polymorphic filamentous strains observed experimentally.