Discrete Molecular Dynamics Study of Aβ16-22 Folding and Aggregation

Alzheimer’s disease (AD) is the most common cause of late life dementia. Substantial clinical and experimental evidence supports the hypothesis that amyloid β-protein (Aβ) aggregation produces assemblies with potent neurotoxic properties that cause AD. For this reason, it is important to elucidate the structural dynamics of Aβ aggregation at atomic level. We apply the discrete molecular dynamics method coupled with a four-bead protein model to study the aggregation of Aβ16-22, a peptide that contains the Aβ central hydrophobic cluster, Leu17–Ala21, found to be crucial in mediating Aβ assembly. Backbone hydrogen bond interactions are incorporated into the model. Effective hydrophobic and electrostatic interactions between side-chains are parameterized using amino acid-specific hydropathies and net charges. The aggregation of up to 16 Aβ16-22 peptides is studied. The results show that randomly-oriented monomers can aggregate into fibrillar subunits. These subunits consist of multi-layer β-sheets that resemble the well-known cross-β structure as revealed by X-ray diffraction studies of amyloid fibrils. An antiparallel arrangement of β-strands is observed within each β-sheet, which agrees with solid-state NMR studies. In the absence of electrostatic interactions the peptides aggregate into amorphous (disordered) structure, 2 suggesting that the electrostatic interactions are crucial to the antiparallel βsheet organization. Heat capacity calculations show that Aβ16-22 assembly and melting are two-stage processes, a prediction that can be tested experimentally using differential scanning calorimetry. Continued investigation of intermediate assembly states along the fibril formation pathway promises to reveal mechanistic features of Aβ assembly of value in the design of therapeutic agents.