Residual structure in the Alzheimer's disease peptide: probing the origin of a central hydrophobic cluster

Abstract

Background: Structure–function studies on the Alzheimer's disease peptide show that a central hydrophobic cluster – Aβ(17–21), LVFFA – is a prominent structural feature linked to plaque competence. The origin and stability of this cluster was probed in a 17-residue fragment which includes flanking residues that potentially help stabilize the cluster.

Results: After residue substitution, the measurement of pK_as, amide exchange rates and other NMR data show that any coulombic interactions between His14 and Glu22 are not required for the stability of the central hydrophobic cluster. In contrast, a single substitution within the cluster disrupts its integrity and causes the largest pK_a shift for flanking residues, while increasing the solvent accessibility of the backbone.

Conclusions:The integrity of the structurally dominant cluster relies primarily upon local hydrophobic interactions, rather than on interactions between the sidechains of charged flanking residues. Moreover, the conformational disposition of the cluster affects the pK_as of flanking residues, underscoring its structural dominance.