Combined High-Pressure and Multiquantum NMR and Molecular Simulation Propose a Role for N-Terminal Salt Bridges in Amyloid-Beta

Abstract

Several lines of evidence point to the important role of the N-terminal region of amyloid-beta (Aβ) peptide in its toxic aggregation in Alzheimer's disease (AD). It is known that charge-altering modifications such as Ser8 phosphorylation promote Aβ fibrillar aggregation. In this Letter, we combine high-pressure NMR, multiquantum chemical exchange saturation transfer (MQ-CEST) NMR, and microseconds-long molecular dynamics simulation and provide evidence of the presence of several salt bridges between Arg5 and its nearby negatively charged residues, in particular, Asp7 and Glu3. The presence of these salt bridges is correlated with less extended structures in the N-terminal region of Aβ. Through density functional theory calculations, we demonstrate how the introduction of negatively charged phosphoserine 8 influences the network of adjacent salt bridges in Aβ and favors more extended N-terminal structures. Our data propose a structural mechanism for the Ser8-phosphorylation-promoted Aβ aggregation and define the N-terminal salt bridges as potential targets for anti-AD drug design.