Nucleation of Polymorphic Amyloid Fibrils

Auer, Stefan

doi:10.1016/j.bpj.2015.01.013

Cited by 14 publications

(32 citation statements)

References 61 publications

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“…ref. 45 ). Thus, the main effect of decreasing the hydrophobicity-mediated interactions ψ h is that it increases the solubilities C e and C iβ for i > 1, but does not alter the metanucleation border C 1β .…”

Section: Resultsmentioning

confidence: 99%

Amyloid Fibril Solubility

Rizzi

Auer

2015

J. Phys. Chem. B

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It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain side-chain interactions, backbone hydrogen bonding and temperature affect amyloid fibril solubility, which might prove a powerful tool to design protein fibrils with desired solubility and aggregation properties in general.

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Section: Resultsmentioning

confidence: 99%

Amyloid Fibril Solubility

Rizzi

Auer

2015

J. Phys. Chem. B

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“…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 . This mechanism is also present in protein fibrils, because the cluster must reach a minimum size of four β‐strands before incoming molecules can form both the H‐bonding and steric‐zipper interactions found in mature fibrils . This means that the second and third β‐strands to add to the cluster sacrifice translational entropy, without the benefit of the full set of attractive interactions found in a mature fibril.…”

Section: Introductionmentioning

confidence: 99%

“…[17] This mechanism is also present in protein fibrils, because the cluster must reach a minimum size of four b-strands before incoming molecules can form both the H-bonding and stericzipper interactions found in mature fibrils. [18][19][20][21] This means that the second and third b-strands to add to the cluster sacrifice translational entropy, without the benefit of the full set of attractive interactions found in a mature fibril. However, in amyloid fibrils, a second contribution to the nucleation barrier appears from the conformational entropy cost of extending the peptide backbones into b-sheets.…”

Section: Introductionmentioning

confidence: 99%

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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“…Most generally, the filamentous self-assembly of protein is a particular case of formation and growth of condensed phases during first-order phase transitions. Despite that this was recognized long ago (12,14,15,37), hitherto, general results of droplet or crystal nucleation and growth theories have relatively rarely been employed in thermodynamic and kinetic studies of protein fibrillation (e.g., see the literature (5,(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)). In particular, the OK model has not been analyzed from the viewpoint of nucleation theory to verify whether it admits of nucleation, and if so, to determine the fibril nucleation barrier and rate.…”

Section: Introductionmentioning

confidence: 99%

Protein Polymerization into Fibrils from the Viewpoint of Nucleation Theory

Kashchiev

2015

Biophysical Journal

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The assembly of various proteins into fibrillar aggregates is an important phenomenon with wide implications ranging from human disease to nanoscience. Using general kinetic results of nucleation theory, we analyze the polymerization of protein into linear or helical fibrils in the framework of the Oosawa-Kasai (OK) model. We show that while within the original OK model of linear polymerization the process does not involve nucleation, within a modified OK model it is nucleation-mediated. Expressions are derived for the size of the fibril nucleus, the work for fibril formation, the nucleation barrier, the equilibrium and stationary fibril size distributions, and the stationary fibril nucleation rate. Under otherwise equal conditions, this rate decreases considerably when the short (subnucleus) fibrils lose monomers much more frequently than the long (supernucleus) fibrils, a feature that should be born in mind when designing a strategy for stymying or stimulating fibril nucleation. The obtained dependence of the nucleation rate on the concentration of monomeric protein is convenient for experimental verification and for use in rate equations accounting for nucleation-mediated fibril formation. The analysis and the results obtained for linear fibrils are fully applicable to helical fibrils whose formation is describable by a simplified OK model.

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Nucleation of Polymorphic Amyloid Fibrils

Cited by 14 publications

References 61 publications

Amyloid Fibril Solubility

Amyloid Fibril Solubility

Theory of Amyloid Fibril Nucleation from Folded Proteins

Protein Polymerization into Fibrils from the Viewpoint of Nucleation Theory

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