The aggregation of β-amyloid (Aβ) peptides has been confirmed to be associated with the onset of Alzheimer's disease (AD). Among the three phases of Aβ aggregation, the lag phase has been considered to be the best time for early Aβ pathological deposition clinical intervention and prevention for potential patients with normal cognition. Aβ peptide exists in various lengths in vivo, and Aβ oligomer in the early lag phase is neurotoxic but polymorphous and metastable, depending on Aβ length (isoform), molecular weight, and specific phase, and therefore hardly characterized experimentally. To cope with the problem, molecular dynamics simulation was used to investigate the aggregation process of five monomers for each of the seven common Aβ isoforms during the lag phase. Results showed that Aβ(1-40) and Aβ(1-38) monomers aggregated faster than their truncated analogues Aβ(4-40) and Aβ(4-38), respectively. However, the aggregation rate of Aβ(1-42) was slower than that of its truncated analogues Aβ(4-42) rather than that of Aβpe(3-42). More importantly, Aβ(1-38) is first predicted as more likely to form stable hexamer than the remaining five Aβ isoforms, as Aβ(1-42) does. It is hydrophobic interaction mainly (>50%) from the interfacial β1 and β2 regions of two reactants, pentamer and monomer, aggregated by Aβ(1-38)/Aβ(1-42) rather than by other Aβ isoforms, that drives the hexamer stably as a result of the formation of the effective hydrophobic collapse. This paper provides new insights into the aggregation characteristics of Aβ with different lengths and the conditions necessary for Aβ to form oligomers with a high molecular weight in the early lag phase, revealing the dependence of Aβ hexamer formation on the specific interfacial interaction.
Keywords: aggregation kinetics; interfacial interaction; metastable state; seven Aβ isoforms; terminal residues.