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Surveying the Energy Landscapes of A? Fibril Polymorphism.

ABSTRACT: Many unrelated proteins and peptides have been found spontaneously to form amyloid fibers above a critical concentration. Even for a single sequence, however, the amyloid fold is not a single well-defined structure. Although the cross-? hydrogen bonding pattern is common to all amyloids, all other aspects of amyloid fiber structures are sensitive to both the sequence of the aggregating peptides and the solvent conditions under which the aggregation occurs. Amyloid fibers are easy to identify and grossly characterize using microscopy, but their insolubility and aperiodicity along the dimensions transverse to the fiber axis have complicated detailed experimental structural characterization. In this paper, we explore the landscape of possibilities for amyloid protofilament structures that are made up of a single stack of peptides associated in a parallel in-register manner. We view this landscape as a two-dimensional version of the usual three-dimensional protein folding problem: the survey of the two-dimensional folds of protein ribbons. Adopting this view leads to a practical method of predicting stable protofilament structures of arbitrary sequences. We apply this scheme to variants of A?, the amyloid forming peptide that is characteristically associated with Alzheimer's disease. Consistent with what is known from experiment, we find that A? protofibrils are polymorphic. To our surprise, however, the ribbon-folding landscape of A? turned out to be strikingly simple. We confirm that, at the level of the monomeric protofilament, the landscape for the A? sequence is reasonably well funneled toward structures that are similar to those that have been determined by experiment. The landscape has more distinct minima than does a typical globular protein landscape but fewer and deeper minima than the landscape of a randomly shuffled sequence having the same overall composition. It is tempting to consider the possibility that the significant degree of funneling of A?'s ribbon-folding landscape has arisen as a result of natural selection. More likely, however, the intermediate complexity of A?'s ribbon-folding landscape has come from the post facto selection of the A? sequence as an object of study by researchers because only by having a landscape with some degree of funneling can ordered aggregation of such a peptide occur at in vivo concentrations. In addition to predicting polymorph structures, we show that predicted solubilities of polymorphs correlate with experiment and with their elongation free energies computed by coarse-grained molecular dynamics.

SUBMITTER: Chen M

PROVIDER: S-EPMC6713213 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Surveying the Energy Landscapes of Aβ Fibril Polymorphism.

Chen Mingchen M Schafer Nicholas P NP Wolynes Peter G PG

The journal of physical chemistry. B 20181001 49

Many unrelated proteins and peptides have been found spontaneously to form amyloid fibers above a critical concentration. Even for a single sequence, however, the amyloid fold is not a single well-defined structure. Although the cross-β hydrogen bonding pattern is common to all amyloids, all other aspects of amyloid fiber structures are sensitive to both the sequence of the aggregating peptides and the solvent conditions under which the aggregation occurs. Amyloid fibers are easy to identify and ...[more]

PMID: 30215519

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Project description: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 Aβ 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 Aβ 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 Aβ9-40 amyloid fibril models based on solid-state NMR experiments. Besides shedding new light on the molecular origins of structural polymorphism in WT Aβ 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.

Dataset Information

Surveying the Energy Landscapes of A? Fibril Polymorphism.

Publications

Surveying the Energy Landscapes of Aβ Fibril Polymorphism.

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