Nucleated polymerization with secondary pathways. III. Equilibrium behavior and oligomer populations

Cohen, Samuel I.; Vendruscolo, Michele; Dobson, Christopher M.; Knowles, Tuomas P. J.

doi:10.1063/1.3608918

Cited by 99 publications

(117 citation statements)

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“…23,36,[42][43][44][45] Here, the term "spontaneous" refers to the fact that the random formation of the smallest growth-competent aggregates (nuclei) occurs directly from solution, without the participation of surfaces or nucleation seeds. A particularly useful approach to understand the way in which soluble proteins are converted into their fibrillar counterparts through spontaneous nucleation is represented by kinetic models of filamentous growth 6,41,43,[46][47][48] . These kinetic models allow the underlying molecular-level mechanisms of fibril formation to be connected with in vitro experimental measurements of the aggregate mass concentration e.g.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of spontaneous filament nucleation via oligomers: Insights from theory and simulation

Šarić

Michaels

Zaccone

et al. 2016

The Journal of Chemical Physics

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Nucleation processes are at the heart of a large number of phenomena, from cloud formation to protein crystallization. A recently emerging area where nucleation is highly relevant is the initiation of filamentous protein self-assembly, a process that has broad implications in many research areas ranging from medicine to nanotechnology. As such, spontaneous nucleation of protein fibrils has received much attention in recent years with many theoretical and experimental studies focussing on the underlying physical principles. In this paper we make a step forward in this direction and explore the early time behaviour of filamentous protein growth in the context of nucleation theory. We first provide an overview of the thermodynamics and kinetics of spontaneous nucleation of protein filaments in the presence of one relevant degree of freedom, namely the cluster size.In this case, we review how key kinetic observables, such as the reaction order of spontaneous nucleation, are directly related to the physical size of the critical nucleus. We then focus on the increasingly prominent case of filament nucleation that includes a conformational conversion of the nucleating building-block as an additional slow step in the nucleation process. Using computer simulations, we study the concentration dependence of the nucleation rate. We find that, under these circumstances, the reaction order of spontaneous nucleation with respect to the free monomer does no longer relate to the overall physical size of the nucleating aggregate but rather to the portion of the aggregate that actively participates in the conformational conversion. Our results thus provide a novel interpretation of the common kinetic descriptors of protein filament formation, including the reaction order of the nucleation step or the scaling exponent of lag times, and put into perspective current theoretical descriptions of protein aggregation.2

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Section: Introductionmentioning

confidence: 99%

Kinetics of spontaneous filament nucleation via oligomers: Insights from theory and simulation

Šarić

Michaels

Zaccone

et al. 2016

The Journal of Chemical Physics

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“…The effect of an hypothetical secondary process that creates new structures of a critical size n 2 through "nucleation" on the surface of existing polymers was also discussed by Cohen and coworkers [11,12]. If n 2 ≈ n c , the distribution is expected to be of qualitatively similar form, with an equilibrium distribution of the exponential type as in the case of a system with primary nucleation [11,12].…”

Section: Discussionmentioning

confidence: 87%

“…As discussed in [12], for systems with a constant concentration of total protein (free monomers plus monomeric units included in polymers) that encompass nucleation, polymerization and fragmentation, the concentration of polymers of each size can be written at steady state t = ∞ as c i P = n c ((n c − 1) n c ) i−nc n c − n 2 c + i + i 2 n 2 c − 1 ! (1 + (n c − 1) n c + i)!…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Size Distribution of Amyloid Fibrils. Mathematical Models and Experimental Data

Prigent¹,

Haffaf²,

Banks³

et al. 2014

Int. J. of Pure and Appl. Math.

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More than twenty types of proteins can adopt misfolded conformations, which can co-aggregate into amyloid fibrils, and are related to pathologies such as Alzheimer's disease. This article surveys mathematical models for aggregation chain reactions, and discuss the ability to use them to understand amyloid distributions. Numerous reactions have been proposed to play a role in their aggregation kinetics, though the relative importance of each reaction in vivo is unclear: these include activation steps, with nucleation compared to initiation, disaggregation steps, with depolymerization compared to fragmentation, and additional processes such as filament coalescence or secondary nucleation. We have statistically analysed the shape of the size distribution of prion fibrils, with the specific example of truncated data due to the experimental technique (electron microscopy). A model of polymerization and depolymerization succeeds in explaining this distribution. It is a very plausible scheme though, as evidenced in the review of other mathematical models, other types of reactions could also give rise to the same type of distributions.

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“…Dusa et al used agitation at 120 rpm in contrast to 1250 rpm that we have used. Although not conclusive, these differences may significantly influence the role of secondary nucleation events in the formation of oligomers, as discussed extensively by Knowles and coworkers [90][91][92].…”

Section: Structurementioning

confidence: 98%

Parkinson's disease in the spotlight : unraveling nanoscale alpha-synuclein oligomers using ultrasensitive single-molecule spectroscopy

Zijlstra¹

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Niels ZijlstraParkinson's disease in the spotlight Protein folding is an extraordinarily complex process of which the details are still unclear, but is thought to be governed by the energy landscape of the protein and involves a stochastic sampling of many different folds, or conformations, until the protein reaches its thermodynamically most favorable fold [7]. This fold is usually called the native structure of the protein and is mainly determined by the amino acid sequence of the protein [8,9], although the complex environment found in a cell is thought to influence the folding as well [10].The folding of a protein is in some cases co-translational, that is, the folding takes place during synthesis [7,11,12]. In other cases, however, the protein folds in the cytoplasm after a complete synthesis, or is first transported to specific parts of the cell, such as mitochondria or the endoplasmic reticulum, before it folds, see figure 1.1 [7,12].Given the complexity of protein folding and the enormous number of folding events in a cell, it is not surprising that sometimes a protein does not fold correctly or that a protein does not stay folded correctly [1,13]. The protein can get trapped in a local energy minimum resulting in the protein to misfold making the protein toxic [1,14].The more complex the protein folding pathway is, the more likely it is that the folding goes wrong. Normally, a cell can minimize the amount of misfolded proteins by using specialized molecular chaperones or folding catalysts to assist in the folding [4,13]. If the folding still goes wrong, the cell can get rid of the misfolded proteins by degrading them via the ubiquitin-proteasome system, see figure 1.1 [15]. Unfortunately, this defense mechanism does not always work properly. 6 1 1.2. Amyloid diseases and the oligomeric species Amyloid diseases and the oligomeric speciesProtein misfolding and the subsequent aggregation is considered to play an important role in many human neurodegenerative diseases, such as Parkinson's, Alzheimer's, and Huntington's disease, type II diabetes, and in the prion diseases [16]. These diseases are associated with the formation of inter-and intracellular inclusions that mainly contain insoluble amyloid fibrillar aggregates. Amyloid refers to the aggregates having a characteristic cross-β sheet secondary structure. These fibrils are ∼10 nm 7 1 1.2. Amyloid diseases and the oligomeric species in diameter, and can be several microns in length, and thus are composed of many thousands of the constituent monomeric proteins [17]. A commonly used method to detect the formation of amyloid aggregates uses the fluorescent dye Thioflavin T (ThioT). When ThioT binds to β-sheet-rich domains, the dye displays enhanced fluorescence intensity and a characteristic red shift of its emission spectrum. ThioT fluorescence is often used to monitor the kinetics of amyloid formation, which, in general, follows a sigmoidal growth curve that is characterized by an initial lag phase, followed by an exponential growth until it reaches a ...

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Nucleated polymerization with secondary pathways. III. Equilibrium behavior and oligomer populations

Cited by 99 publications

References 48 publications

Kinetics of spontaneous filament nucleation via oligomers: Insights from theory and simulation

Kinetics of spontaneous filament nucleation via oligomers: Insights from theory and simulation

Size Distribution of Amyloid Fibrils. Mathematical Models and Experimental Data

Parkinson's disease in the spotlight : unraveling nanoscale alpha-synuclein oligomers using ultrasensitive single-molecule spectroscopy

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