Perturbation of the Stability of Amyloid Fibrils through Alteration of Electrostatic Interactions

Sarah L. Shammas, Tuomas P. J. Knowles, Andrew J. Baldwin, Cait E. MacPhee, Mark E. Welland, Christopher M. Dobson, Glyn L. Devlin

Research output: Contribution to journalArticlepeer-review

Abstract

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-beta 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-beta 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.

Original languageEnglish
Pages (from-to)2783-2791
Number of pages9
JournalBiophysical Journal
Volume100
Issue number11
DOIs
Publication statusPublished - 8 Jun 2011

Keywords

  • MOLECULAR-PROPERTIES
  • SECONDARY STRUCTURE
  • POLYPEPTIDE-CHAINS
  • AGGREGATION RATES
  • BOVINE INSULIN
  • PROTEIN
  • PEPTIDE
  • THERMODYNAMICS
  • FIBRILLATION
  • MUTAGENESIS

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