Cross-strand pairing and amyloid assembly

Amino acid cross-strand pairing interactions along a β-sheet surface have been implicated in protein β-structural assembly and stability, yet the relative contributions have been difficult to evaluate directly. Here we develop the central core sequence of the Aβ peptide associated with Alzheimer's disease, Aβ(16-22), as an experimental system for evaluating these interactions. The peptide allows for internal comparisons between electrostatic and steric interactions within the β-sheet and an evaluation of these cross-strand pair contributions to β-sheet registry. A morphological transition from fibers to hollow nanotubes arises from changes in β-sheet surface complementarity and provides a convenient indicator of the β- strand strand registry. The intrinsic β-sequence and pair correlations are critical to regulate secondary assembly. These studies provide evidence for a critical desolvation step that is not present in most models of the nucleation-dependent pathway for amyloid assembly.