Discrete Molecular Dynamics Study of wild-type and Arctic-mutant (E22G) Aβ16−22 Folding and Aggregation

Substantial clinical and experimental evidence supports the hypothesis that amyloid β-protein (Aβ) forms assemblies with potent neurotoxic properties that cause Alzheimer’s disease (AD). Therapeutic targeting of these assemblies would be facilitated by the elucidation of the structural dynamics of Aβ aggregation at atomic resolution. We apply the ab initio discrete molecular dynamics approach coupled with a four-bead peptide model to study the aggregation of wild-type and Arctic-mutant (E22G) Aβ16−22, a peptide that contains the Aβ central hydrophobic cluster, Leu17–Ala21, that plays an important role in Aβ assembly. The aggregation of sixteen wild-type Aβ16−22 peptides is studied systematically under solvent conditions incorporating: (i) effective hydropathic and electrostatic interactions; (ii) no effective hydropathic interactions; and (iii) no effective electrostatic interactions. We find that at physiological temperatures initially-separated peptides aggregate into fibrillar units under condition (i). These units comprise multi-layered β-sheets with cross-β structure and an antiparallel arrangement of β-strands. Under condition (iii), β-strands are arranged either in a parallel or antiparallel manner, suggesting that electrostatic interactions control β-sheet organization. For condition (ii), no fully-formed fibrillar aggregates are observed, only occasional antiparallel β-strands. Fibrillar aggregates of Arctic-mutant Aβ16−22 peptides have parallel as well as antiparallel β-strands resembling the aggregates of wild-type Aβ16−22 peptides with no electrostatic interaction. We find that flexibility of peptide backbone is an important factor required for fibrillization. Arctic-mutant Aβ16−22 peptides oligomerize slower due to negligible role of electrostatic interaction in driving oligomerization, but fibrillize faster due to greater flexibility and ease of rearrangement with smaller volume and no charge of G22 than wild-type. It implies that electrostatic interaction cooperatively drives initial oligomerization of Aβ with hydropathic interaction.