Protein misfolding is now implicated in at least fifty disease states, and among these, the neurodegenerative diseases are a personal and societal tragedy of large and growing proportions. Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder, emerges from the misfolding and accumulation of disease-specific proteins in the brain: Aβ in senile plaques and cerebral amyloid angiopathy, and tau in neurofibrillary tangles. Recent insight into AD therapeutic intervention has highlighted Aβ clearance, and three key observations have emerged: (i) a remarkable diversity of structures are accessible to a given protein sequence, and the resulting aggregates are structurally and functionally distinct; (ii) from this varied collection of possible assemblies, individual forms propagate through a conformational ‘Darwinian selection’ process to yield distinct strains; and (iii) pathogenic protein conformers can cross-seed the misfolding and aggregation of other proteins, yielding diverse and sometimes complex folding pathways highly susceptible to environmental perturbations. We will discuss how covalent macromolecular synthesis can be tied to non-covalent folding and supramolecular associations in a single molecular scaffold, and define critical chemical and physical functions emerging from the tensions inherent in dynamic chemical/physical networks. These results argue that the range and degree of order accessible to various co-assemblies can yield diverse functional phases, from compartments to metabolism and informational polymers, and suggest that specific phases can be propagated and selected in disease or exploited for needed structural and chemical material functions.

Environmental influence on assembly landscapes in protein materials

253rd National Meeting (2017)

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