CUED Publications database

Perturbation of the stability of amyloid fibrils through alteration of electrostatic interactions.

Shammas, SL and Knowles, TPJ and Baldwin, AJ and Macphee, CE and Welland, ME and Dobson, CM and Devlin, GL (2011) Perturbation of the stability of amyloid fibrils through alteration of electrostatic interactions. Biophys J, 100. pp. 2783-2791.

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The self-assembly of proteins and peptides into polymeric amyloid fibrils is a process that has important implications ranging from the understanding of protein misfolding disorders to the discovery of novel nanobiomaterials. In this study, we probe the stability of fibrils prepared at pH 2.0 and composed of the protein insulin by manipulating electrostatic interactions within the fibril architecture. We demonstrate that strong electrostatic repulsion is sufficient to disrupt the hydrogen-bonded, cross-β network that links insulin molecules and ultimately results in fibril dissociation. The extent of this dissociation correlates well with predictions for colloidal models considering the net global charge of the polypeptide chain, although the kinetics of the process is regulated by the charge state of a single amino acid. We found the fibrils to be maximally stable under their formation conditions. Partial disruption of the cross-β network under conditions where the fibrils remain intact leads to a reduction in their stability. Together, these results support the contention that a major determinant of amyloid stability stems from the interactions in the structured core, and show how the control of electrostatic interactions can be used to characterize the factors that modulate fibril stability.

Item Type: Article
Uncontrolled Keywords: Amino Acid Sequence Amyloid Hydrogen-Ion Concentration Insulin Kinetics Molecular Sequence Data Protein Multimerization Protein Stability Protein Structure, Secondary Static Electricity Thermodynamics
Divisions: Div B > Solid State Electronics and Nanoscale Science
Depositing User: Cron Job
Date Deposited: 17 Jul 2017 19:11
Last Modified: 21 Jun 2018 02:27