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Amyloid Fibril Design: Limiting Structural Polymorphism in Alzheimer’s Aβ Protofilaments

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posted on 18.10.2018, 00:00 by Bartłomiej Tywoniuk, Ye Yuan, Sarah McCartan, Beata Maria Szydłowska, Florentina Tofoleanu, Bernard R. Brooks, Nicolae-Viorel Buchete
Nanoscale fibrils formed by amyloid peptides have a polymorphic character, adopting several types of molecular structures in similar growth conditions. As shown by experimental (e.g., solid-state NMR) and computational studies, amyloid fibril polymorphism hinders both the structural characterization of Alzheimer’s amyloid protofilaments and fibrils at a molecular level, as well as the possible applications (e.g., development of drugs or biomarkers) that rely on similar, controlled molecular arrangements of the peptides in amyloid fibril structures. We have explored the use of several contact potentials for the efficient identification of minimal sequence mutations that could enhance the stability of specific fibril structures while simultaneously destabilizing competing topologies, controlling thus the amount of structural polymorphism in a rational way. We found that different types of contact potentials, while having only partial accuracy on their own, lead to similar results regarding ranking the compatibility of wild-type (WT) and mutated amyloid sequences with different fibril morphologies. This approach allows exhaustive screening and assessment of possible mutations and the identification of minimal consensus mutations that could stabilize fibrils with the desired topology at the expense of other topology types, a prediction that is further validated using atomistic molecular dynamics with explicit water molecules. We apply this two-step multiscale (i.e., residue and atomistic-level) approach to predict and validate mutations that could bias either parallel or antiparallel packing in the core Alzheimer’s 9–40 amyloid fibril models based on solid-state NMR experiments. Besides shedding new light on the molecular origins of structural polymorphism in WT fibrils, our study could also lead to efficient tools for assisting future experimental approaches for amyloid fibril determination, and for the development of biomarkers or drugs aimed at interfering with the stability of amyloid fibrils, as well as for the future design of amyloid fibrils with a controlled (e.g., reduced) level of structural polymorphism.

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