Delving into the crucial role of the initial structure in the dynamic and self-assembly of amyloid beta

Alzheimer's disease involves the accumulation of amyloid beta (Aβ) monomers that form oligomers and fibrils in the brain. Studying the Aβ monomer is critical for understanding Aβ assembly and peptide behavior and has implications for drug design. Choosing a starting structure with a higher aggregation tendency for cost-effective MD studies and drug design is crucial. Previous studies have utilized distinct initial conformations, leading to varying results. Hence, this study was conducted to compare different initial conformations using the same MD simulation protocol to investigate the behavior and oligomerization propensity of different starting structures of Aβ during 1μs. The behavior of the monomers and their self-assembly systems were studied thoroughly, and the results revealed that highly helical Aβ monomers which used as starting structures retain high helix content during the simulation, and their tautomerization states did not cause significant changes in the structure. On the other hand, the Aβ extended and S-shaped monomers displayed the fingerprints of the fibril structure, which is believed to be more favorable for self-assembly. Self-assembly behaviors were seen for three S-shaped and three Aβ extended peptides. However, both conformations did not show stable β-sheet intermolecular interaction. For the Aβ16-22 monomer as a fragment of the Aβ that can assemble into fibrils, the impacts of capping and uncapping on the initial structure were also investigated. The results displayed that capped and uncapped structures can form oligomers with β-sheet at termini. However, in the capped state, β-sheet interactions were more stable and remained relatively longer than uncapped.