Pseudo-one-dimensional nucleation in dilute polymer solutions

Zhang, Lingyun; Schmit, Jeremy D.

doi:10.1103/physreve.93.060401

Cited by 21 publications

(25 citation statements)

References 39 publications

(35 reference statements)

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“…These H‐bonds constrain a segment of each peptide into the extended β‐sheet conformation. The entropic cost of this constraint exceeds the binding energy of the bonds, so that the dimer has a net unfavorable free energy . The protein segments not constrained by intermolecular bonds are free to adopt either folded or random‐coil conformations.…”

Section: Modelmentioning

confidence: 99%

“…To describe the nucleation time, we modify the rate equation from classical nucleation theory, as described previously:

true k_{normals normals} = \sum_{m_{3} = 1}^{L} k_{normalo normaln} c_{1} c_{3} ((), m_{3}) ℰ_{1} ((), m_{3})

true k_{normalh normalp} = \sum_{m_{h p} = 1}^{\frac{L}{2}} k_{normalo normaln} c_{1} c_{h p} ((), m_{h p}) ℰ_{1} ((), 2, m_{h p}) .

…”

Section: Modelmentioning

confidence: 99%

“…In a recent paper, we used the H‐bond reaction coordinate to model the lag times that precede the onset of aggregation . In classical nucleation theory, the lag time is a result of the fact that an aggregating cluster must reach a critical size before the favorable energy of binding is able to offset the translational entropy cost of being confined to the cluster .…”

Section: Introductionmentioning

confidence: 99%

“…However, in amyloid fibrils, a second contribution to the nucleation barrier appears from the conformational entropy cost of extending the peptide backbones into β‐sheets . The magnitude of this entropic penalty is such that fibrils must reach a length of ∼5 β‐strands before the free energy of the fibril is lower than that of the soluble monomers …”

Section: Introductionmentioning

confidence: 99%

“…Our previous theory shows that the dominant nucleation pathway is a compromise between two competing effects . On one hand, prenucleation clusters will seek low free‐energy states that maximize conformational disorder.…”

Section: Introductionmentioning

confidence: 99%

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Theory of Amyloid Fibril Nucleation from Folded Proteins

Zhang

Schmit

2017

Israel Journal of Chemistry

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We present a theoretical model for the nucleation of amyloid fibrils. In our model we use helix-coil theory to describe the equilibrium between a soluble native state and an aggregation-prone unfolded state. We then extend the theory to include oligomers with β-sheet cores and calculate the free energy of these states using estimates for the energies of H-bonds, steric zipper interactions, and the conformational entropy cost of forming secondary structure. We find that states with fewer than ~10 β-strands are unstable relative to the dissociated state and three β-strands is the highest free energy state. We then use a modified version of Classical Nucleation Theory to compute the nucleation rate of fibrils from a supersaturated solution of monomers, dimers, and trimers. The nucleation rate has a non-monotonic dependence on denaturant concentration reflecting the competing effects of destabilizing the fibril and increasing the concentration of unfolded monomers. We estimate heterogeneous nucleation rates and discuss the application of our model to secondary nucleation.

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Section: Modelmentioning

confidence: 99%

“…To describe the nucleation time, we modify the rate equation from classical nucleation theory, as described previously:

true k_{normals normals} = \sum_{m_{3} = 1}^{L} k_{normalo normaln} c_{1} c_{3} ((), m_{3}) ℰ_{1} ((), m_{3})

true k_{normalh normalp} = \sum_{m_{h p} = 1}^{\frac{L}{2}} k_{normalo normaln} c_{1} c_{h p} ((), m_{h p}) ℰ_{1} ((), 2, m_{h p}) .

…”

Section: Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Theory of Amyloid Fibril Nucleation from Folded Proteins

Zhang

Schmit

2017

Israel Journal of Chemistry

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Thermodynamics of Huntingtin Aggregation

Phan

Schmit

2020

Biophysical Journal

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Amyloid aggregates are found in many neurodegenerative diseases, including Huntington's, Alzheimer's, and prion diseases. The precise role of the aggregates in disease progression has been difficult to elucidate because of the diversity of aggregated states they can adopt. Here, we study the formation of fibrils and oligomers by exon 1 of huntingtin protein. We show that the oligomer states are consistent with polymer micelles that are limited in size by the stretching entropy of the polyglutamine region. The model shows how the sequences flanking the amyloid core modulate aggregation behavior. The N17 region promotes aggregation through weakly attractive interactions, whereas the C38 tail opposes aggregation via steric repulsion. We also show that the energetics of cross-b stacking by polyglutamine would produce fibrils with many alignment defects, but minor perturbations from the flanking sequences are sufficient to reduce the defects to the level observed in experiment. We conclude with a discussion of the implications of this model for other amyloid-forming molecules.

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Mechanics of a molecular mousetrap—nucleation-limited innate immune signaling

Gama

Miller²,

Halfmann³

2021

Biophysical Journal

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Innate immune responses, such as cell death and inflammatory signaling, are typically switch-like in nature. They also involve ''prion-like'' self-templating polymerization of one or more signaling proteins into massive macromolecular assemblies known as signalosomes. Despite the wealth of atomic-resolution structural information on signalosomes, how the constituent polymers nucleate and whether the switch-like nature of that event at the molecular scale relates to the digital nature of innate immune signaling at the cellular scale remains unknown. In this perspective, we review current knowledge of innate immune signalosome assembly, with an emphasis on structural constraints that allow the proteins to accumulate in inactive soluble forms poised for abrupt polymerization. We propose that structurally encoded nucleation barriers to protein polymerization kinetically regulate the corresponding pathways, which allows for extremely sensitive, rapid, and decisive signaling upon pathogen detection. We discuss how nucleation barriers satisfy the rigorous on-demand functions of the innate immune system but also predispose the system to precocious activation that may contribute to progressive age-associated inflammation.

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Pseudo-one-dimensional nucleation in dilute polymer solutions

Cited by 21 publications

References 39 publications

Theory of Amyloid Fibril Nucleation from Folded Proteins

Theory of Amyloid Fibril Nucleation from Folded Proteins

Thermodynamics of Huntingtin Aggregation

Mechanics of a molecular mousetrap—nucleation-limited innate immune signaling

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