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