Preformed Seeds Modulate Native Insulin Aggregation Kinetics

Dutta, Colina; Yang, Miao; Long, Fei; Shahbazian‐Yassar, Reza; Tiwari, Ashutosh

doi:10.1021/acs.jpcb.5b07221

Cited by 14 publications

(13 citation statements)

References 69 publications

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“…Several studies suggest that increasing the concentration of seed available (via secondary nucleation, sonication-induced fragmentation, or increased initial concentration) decreases the lag time of fibrillogenesis. [39][40][41] However, in our case, there is a slight increase in the lag time with increases in the ratio of f 0 * to m 0 when m 0 is in excess. The observed increase in lag time can likely be attributed to differences in the nature of dock-lock reaction mechanism (3).…”

Section: Discussioncontrasting

confidence: 57%

Estimation of the lag time in a subsequent monomer addition model for fibril elongation

Shoffner

Schnell

2016

Phys. Chem. Chem. Phys.

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Fibrillogenesis, the production or development of protein fibers, has been linked to protein folding diseases. The progress curve of fibrils or aggregates typically takes on a sigmoidal shape with a lag phase, a rapid growth phase, and a final plateau regime. The study of the lag phase and the estimation of its critical timescale provide insight into the factors regulating the fibrillation process. However, methods to estimate a quantitative expression for the lag time rely on empirical expressions, which cannot connect the lag time to kinetic parameters associated with the reaction mechanisms of protein fibrillation. Here we introduce an approach for the estimation of the lag time using the governing rate equations of the elementary reactions of a subsequent monomer addition model for protein fibrillation as a case study. We show that the lag time is given by the sum of the critical timescales for each fibril intermediate in the subsequent monomer addition mechanism and therefore reveals causal connectivity between intermediate species. Furthermore, we find that single-molecule assays of protein fibrillation can exhibit a lag phase without a nucleation process, while dyes and extrinsic fluorescent probe bulk assays of protein fibrillation do not exhibit an observable lag phase during template-dependent elongation. Our approach could be valuable for investigating the effects of intrinsic and extrinsic factors to the protein fibrillation reaction mechanism and provides physicochemical insights into parameters regulating the lag phase.

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Section: Discussioncontrasting

confidence: 57%

Estimation of the lag time in a subsequent monomer addition model for fibril elongation

Shoffner

Schnell

2016

Phys. Chem. Chem. Phys.

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“…Similar data on the formation of nonspecific oligomers of insulin in the presence of inhibitors have been recently reported. 40,43 Because preformed seeds are known to modulate insulin aggregation kinetics, 45 we further examined the effect of these AuNPs piperine on seed-induced fibril assembly of insulin.…”

Section: Resultsmentioning

confidence: 99%

Uniform, Polycrystalline, and Thermostable Piperine-Coated Gold Nanoparticles to Target Insulin Fibril Assembly

Anand

Shekhawat

Dubey

et al. 2017

ACS Biomater. Sci. Eng.

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Because the process of insulin fibril assembly is linked to a multitude of medical problems, finding effective and biocompatible inhibitors against such an aggregation process could be beneficial. Targeting the aggregation-prone residues of insulin may perhaps work as an effective strategy to prevent the onset of insulin fibril assembly. In this work, we have synthesized uniform sized, thermostable gold nanoparticles (AuNPs piperine ) surface-functionalized with piperine to target amyloid-prone residues of insulin. We found that the process of both spontaneous and seed-induced amyloid formation of insulin was strongly inhibited in the presence of AuNPs piperine . Surface functionalization of piperine was found to be critical to its inhibition effect because no such effect was observed for free piperine as well as for uncoated control gold nanoparticles. Fluorescence quenching data revealed binding of AuNPs piperine with insulin's native structure which was further validated by docking studies that predicted viable H-bond and CH-π interactions between piperine and key aggregation-prone residues of insulin's B-chain. Our hemolysis assay studies further confirmed that these piperine coated nanoparticles were hemocompatible. Data obtained from both experimental and computational studies suggest that the retention of native structure of insulin and the ability of the piperine molecule to interact with the aggregation-prone residues of insulin are the key factors for the inhibition mechanism. The findings of this work may help in the development of nanoparticle-based formulations to prevent medical problems linked to insulin aggregation.

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“…Several studies suggest that increasing the concentration of seed available (via secondary nucleation, sonication-induced fragmentation, or increased initial concentration) decreases the lag time of fibrillogenesis. [39][40][41] However, in our case, there is a slight increase in the lag time with increases in the ratio of f * 0 to m 0 when m 0 is in excess. The observed increase in lag time can likely be attributed to differences in the nature of dock-lock reaction mechanism (3).…”

Section: Discussionmentioning

confidence: 84%

Estimation of the lag time in a subsequent monomer addition model for fibril elongation

Shoffner

Schnell

2015

Preprint

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Fibrillogenesis, the production or development of protein fibers, has been linked to protein folding diseases. The progress curve of fibrils or aggregates typically takes on a sigmoidal shape with a lag phase, a rapid growth phase, and a final plateau regime. The study of the lag phase and the estimation of its critical timescale provide insight into the factors regulating the fibrillation process. However, methods to estimate a quantitative expression for the lag time rely on empirical expressions, which cannot connect the lag time to kinetic parameters associated with the reaction mechanisms of protein fibrillation. Here we introduce an approach for the estimation of the lag time using the governing rate equations of the elementary reactions of a subsequent monomer addition model for protein fibrillation as a case study. We show that the lag time is given by the sum of the critical timescales for each fibril intermediate in the subsequent monomer addition mechanism and therefore reveals causal connectivity between intermediate species. Furthermore, we find that protein fibrillation can exhibit a lag phase without a nucleation process. Our approach could be valuable for investigating the effects of intrinsic and extrinsic factors to the protein fibrillation reaction mechanism and provides physicochemical insights into parameters regulating the lag phase.

show abstract

Preformed Seeds Modulate Native Insulin Aggregation Kinetics

Cited by 14 publications

References 69 publications

Estimation of the lag time in a subsequent monomer addition model for fibril elongation

Estimation of the lag time in a subsequent monomer addition model for fibril elongation

Uniform, Polycrystalline, and Thermostable Piperine-Coated Gold Nanoparticles to Target Insulin Fibril Assembly

Estimation of the lag time in a subsequent monomer addition model for fibril elongation

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