Aminoacid substitutions in the glycine zipper affect the conformational stability of amyloid beta fibrils

Abstract

The aggregation of amyloid-beta peptides is associated with the pathogenesis of Alzheimer’s disease. The hydrophobic core of the amyloid beta sequence contains a GxxxG repeated motif, called glycine zipper, which involves crucial residues for assuring stability and promoting the process of fibril formation. Mutations in this motif lead to a completely different oligomerization pathway and rate of fibril formation. In this work, we have tested G33L and G37L residue substitutions by molecular dynamics simulations. We found that both protein mutations may lead to remarkable changes in the fibril conformational stability. Results suggest the disruption of the glycine zipper as a possible strategy to reduce the aggregation propensity of amyloid beta peptides. On the basis of our data, further investigations may consider this key region as a binding site to design/discover novel effective inhibitors.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer's disease
• molecular dynamics
• aminoacid mutation
• protein aggregation
• amyloid fibrils

Acknowledgement

This work was supported by a grant from the Swiss National Supercomputing Centre (CSCS).

Disclosure statement

No potential conflict of interest was reported by the authors.