Structural Dynamics of the Amyloid β-Protein Monomer Folding Nucleus

Alzheimer’s disease (AD) is linked to the aberrant assembly of the amyloid β-protein (Aβ). The ²¹AEDVGSNKGA³⁰ segment, Aβ(21–30), forms a turn that acts as a monomer folding nucleus. Amino acid substitutions within this nucleus cause familial forms of AD. To determine the biophysical characteristics of the folding nucleus, we studied the biologically relevant acetyl-Aβ(21–30)-amide peptide using experimental techniques (limited proteolysis, thermal denaturation, urea denaturation followed by pulse proteolysis, and electron microscopy) and computational methods (molecular dynamics). Our results reveal a highly stable foldon and suggest new strategies for therapeutic drug development.