Aggregation Kinetics of Interrupted Polyglutamine Peptides

Walters, Robert H.; Murphy, Regina M.

doi:10.1016/j.jmb.2011.07.003

Cited by 35 publications

(59 citation statements)

References 51 publications

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“…Walters et al have shown in their experiments that while polyQ sequences of a shorter length and those of a longer length form fibers with clear bundles, the fiber morphology of the intermediate length peptides Q 26 shows a lateral alignment. 25 We see that this lateral alignment phenomenon is explained by the present simulations.…”

Section: Resultssupporting

confidence: 75%

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The Aggregation Free Energy Landscapes of Polyglutamine Repeats

et al. 2016

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Aggregates of proteins containing polyglutamine (polyQ) repeats are strongly associated with several neurodegenerative diseases. The length of the repeats correlates with the severity of the disease. Previous studies have shown that pure polyQ peptides aggregate by nucleated growth polymerization and that the size of the critical nucleus (n*) decreases from tetrameric to dimeric and monomeric as length increases from Q18 to Q26. Why the critical nucleus size changes with repeat-length has been unclear. Using the associative memory, water-mediated, structure and energy model, we construct the aggregation free energy landscapes for polyQ peptides of different repeat-lengths. These studies show that the monomer of the shorter repeat-length (Q20) prefers an extended conformation and that its aggregation indeed has a trimeric nucleus (n* ∼ 3), while a longer repeat-length monomer (Q30) prefers a β-hairpin conformation which then aggregates in a downhill fashion at 0.1 mM. For an intermediate length peptide (Q26), there is an equal preference for hairpin and extended forms in the monomer which leads to a mixed inhomogeneous nucleation mechanism for fibrils. The predicted changes of monomeric structure and nucleation mechanism are confirmed by studying the aggregation free energy profile for a polyglutamine repeat with site-specific PG mutations that favor the hairpin form, giving results in harmony with experiments on this system.

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Section: Resultssupporting

confidence: 75%

“…22–25 Circular dichroism (CD) suggests that polyQ peptides are largely disordered and gives little hint of there being any difference between the short polyQ sequences and longer ones. 23,26–28 The CD analysis suggests that Q 40 has about 10% α -helix content and only a trace amount of β -sheet and β -turn.…”

Section: Resultsmentioning

confidence: 99%

The Aggregation Free Energy Landscapes of Polyglutamine Repeats

et al. 2016

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“…Kinetics experiments initiated from fully disaggregated solutions that are supersaturated with respect to c s indicate the early formation of spherical aggregates, 10-30 nm in size, that are precursors of fibrillar aggregates. Fibril formation is barrierlimited and appears to proceed via nucleated conformational conversion within liquid-like spheres [82][83][84] in accord with the mechanism for crystallization that was proposed by ten Wolde and Frenkel. 85 In contrast, the formation of metastable liquidlike spheres does not involve discernible free energy barriers.…”

Section: Application Of Camelot For Simulations Of Block-copolymesupporting

confidence: 72%

CAMELOT: A machine learning approach for coarse-grained simulations of aggregation of block-copolymeric protein sequences

Ruff

Harmon

Pappu

2015

The Journal of Chemical Physics

102

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We report the development and deployment of a coarse-graining method that is well suited for computer simulations of aggregation and phase separation of protein sequences with block-copolymeric architectures. Our algorithm, named CAMELOT for Coarse-grained simulations Aided by MachinE Learning Optimization and Training, leverages information from converged all atom simulations that is used to determine a suitable resolution and parameterize the coarse-grained model. To parameterize a system-specific coarse-grained model, we use a combination of Boltzmann inversion, non-linear regression, and a Gaussian process Bayesian optimization approach. The accuracy of the coarsegrained model is demonstrated through direct comparisons to results from all atom simulations. We demonstrate the utility of our coarse-graining approach using the block-copolymeric sequence from the exon 1 encoded sequence of the huntingtin protein. This sequence comprises of 17 residues from the N-terminal end of huntingtin (N17) followed by a polyglutamine (polyQ) tract. Simulations based on the CAMELOT approach are used to show that the adsorption and unfolding of the wild type N17 and its sequence variants on the surface of polyQ tracts engender a patchy colloid like architecture that promotes the formation of linear aggregates. These results provide a plausible explanation for experimental observations, which show that N17 accelerates the formation of linear aggregates in block-copolymeric N17-polyQ sequences. The CAMELOT approach is versatile and is generalizable for simulating the aggregation and phase behavior of a range of block-copolymeric protein sequences. C 2015 AIP Publishing LLC. [http://dx

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“…These fibrils were identical in morphology to those observed previously for a similar Q-repeat peptide. 29 …”

Section: ■ Resultsmentioning

confidence: 99%

Asparagine Repeat Peptides: Aggregation Kinetics and Comparison with Glutamine Repeats

Lū

Murphy

2015

Biochemistry

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Amino acid repeat runs are common occurrences in eukaryotic proteins, with glutamine (Q) and asparagine (N) as particularly frequent repeats. Abnormal expansion of Q-repeat domains causes at least nine neurodegenerative disorders, most likely because expansion leads to protein misfolding, aggregation, and toxicity. The linkage between Q-repeats and disease has motivated several investigations into the mechanism of aggregation and the role of Q-repeat length in aggregation. Curiously, glutamine repeats are common in vertebrates, whereas N-repeats are virtually absent in vertebrates, but common in invertebrates. One hypothesis for the lack of N-repeats in vertebrates is biophysical; that is, there is strong selective pressure in higher organisms against aggregation-prone proteins. If true, then asparagine and glutamine repeats must differ substantially in their aggregation properties despite their chemical similarities. In this work, aggregation of peptides with asparagine repeats of variable length (12-24) were characterized and compared to that of similar peptides with glutamine repeats. As with glutamine, aggregation of N-repeat peptides was strongly length-dependent. Replacement of glutamine with asparagine caused a subtle shift in the conformation of the monomer, which strongly affected the rate of aggregation. Specifically, N-repeat peptides adopted β-turn structural elements, leading to faster self-assembly into globular oligomers and much more rapid conversion into fibrillar aggregates, compared to Q-repeat peptides. These biophysical differences may account for the differing biological roles of N- versus Q-repeat domains.

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Aggregation Kinetics of Interrupted Polyglutamine Peptides

Cited by 35 publications

References 51 publications

The Aggregation Free Energy Landscapes of Polyglutamine Repeats

The Aggregation Free Energy Landscapes of Polyglutamine Repeats

CAMELOT: A machine learning approach for coarse-grained simulations of aggregation of block-copolymeric protein sequences

Asparagine Repeat Peptides: Aggregation Kinetics and Comparison with Glutamine Repeats

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