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The Levinthal Problem in Amyloid Aggregation: Sampling of a Flat Reaction Space.

ABSTRACT: The formation of amyloid fibrils has been associated with many neurodegenerative disorders, yet the mechanism of aggregation remains elusive, partly because aggregation time scales are too long to probe with atomistic simulations. A microscopic theory of fibril elongation was recently developed that could recapitulate experimental results with respect to the effects of temperature, denaturants, and protein concentration on fibril growth kinetics (Schmit, J. D. J. Chem. Phys. 2013, 138 (18), 185102). The theory identifies the conformational search over H-bonding states as the slowest step in the aggregation process and suggests that this search can be efficiently modeled as a random walk on a rugged one-dimensional energy landscape. This insight motivated the multiscale computational algorithm for simulating fibril growth presented in this paper. Briefly, a large number of short atomistic simulations are performed to compute the system diffusion tensor in the reaction coordinate space predicted by the analytic theory. Ensemble aggregation pathways and growth kinetics are then computed from Markov state model (MSM) trajectories. The algorithm is deployed here to understand the fibril growth mechanism and kinetics of A?16-22 and three of its mutants. The order of growth rates of the wild-type and two single mutation peptides (CHA19 and CHA20) predicted by the MSM trajectories is consistent with experimental results. The simulation also correctly predicts that the double mutation (CHA19/CHA20) would reduce the fibril growth rate, even though the degree of rate reduction with respect to either single mutation is overestimated. This artifact may be attributed to the simplistic implicit solvent model. These trends in the growth rate are not apparent from inspection of the rate constants of individual bonds or the lifetimes of the mis-registered states that are the primary kinetic traps but only emerge in the ensemble of trajectories generated by the MSM.

SUBMITTER: Jia Z

PROVIDER: S-EPMC5573152 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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The Levinthal Problem in Amyloid Aggregation: Sampling of a Flat Reaction Space.

Jia Zhiguang Z Beugelsdijk Alex A Chen Jianhan J Schmit Jeremy D JD

The journal of physical chemistry. B 20170213 7

The formation of amyloid fibrils has been associated with many neurodegenerative disorders, yet the mechanism of aggregation remains elusive, partly because aggregation time scales are too long to probe with atomistic simulations. A microscopic theory of fibril elongation was recently developed that could recapitulate experimental results with respect to the effects of temperature, denaturants, and protein concentration on fibril growth kinetics (Schmit, J. D. J. Chem. Phys. 2013, 138 (18), 1851 ...[more]

PMID: 28129689

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Project description:Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-? plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-? aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-? aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-? aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-? plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.

Dataset Information

The Levinthal Problem in Amyloid Aggregation: Sampling of a Flat Reaction Space.

Publications

The Levinthal Problem in Amyloid Aggregation: Sampling of a Flat Reaction Space.

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