Aggregation Dynamics Characteristics of Seven Different A Oligomeric Isoforms-Dependence on the Interfacial Interaction

The aggregation of beta-amyloid (A beta) peptides has been confirmed to be associated with the onset of Alzheimer's disease (AD). Among the three phases of A beta aggregation, the lag phase has been considered to be the best time for early A beta pathological deposition clinical intervention and prevention for potential patients with normal cognition. A beta peptide exists in various lengths in vivo, and A beta oligomer in the early lag phase is neurotoxic but polymorphous and metastable, depending on A beta 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 A beta isoforms during the lag phase. Results showed that A beta(1-40) and A beta(1-38) monomers aggregated faster than their truncated analogues A beta(4-40) and A beta(4-38), respectively. However, the aggregation rate of A beta(1-42) was slower than that of its truncated analogues A beta(4-42) rather than that of A beta pe(3-42). More importantly, A beta(1-38) is first predicted as more likely to form stable hexamer than the remaining five A beta isoforms, as A beta(1-42) does. It is hydrophobic interaction mainly (>50%) from the interfacial beta 1 and beta 2 regions of two reactants, pentamer and monomer, aggregated by A beta(1-38)/A beta(1-42) rather than by other A beta 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 A beta with different lengths and the conditions necessary for A beta to form oligomers with a high molecular weight in the early lag phase, revealing the dependence of A beta hexamer formation on the specific interfacial interaction.