Preventing amyloid-β oligomerization and aggregation with berberine: Investigating the mechanism of action through computational methods

Neurological disorders (NDs) have become a major cause of both cognitive and physical disabilities worldwide. In NDs, misfolded proteins tend to adopt a β-sheet-rich fibrillar structure called amyloid. Amyloid beta (Aβ) plays a crucial role in the nervous system. The misfolding and aggregation of Aβ are primary factors in the progression of Alzheimer's disease (AD). Inhibiting the oligomerization and aggregation of Aβ is considered as an effective strategy against NDs. While it is known that berberine analogs exhibit anti-Aβ aggregation properties, the precise mechanism of action remains unclear. In this study, we have employed computational approaches to unravel the possible mechanism by which berberine combats Aβ aggregation. The introduction of berberine was observed to delay the equilibrium of Aβ16-21 oligomerization. Initially, within the first 10 ns of simulation, β-sheets content was 12.89 % and gradually increased to 22.19 % within the first 20 ns. This upward trend continued, reaching 32.80 %. However, berberine substantially reduced the formation of β-sheets to 1.36 %. These findings decipher the potency of berberine against Aβ16-21 oligomerization, a crucial step for β-sheet formation. Additionally, a remarkable decrease in total number of hydrogen bonds was found in the presence of berberine. Berberine also led to a slight reduction in the flexibility of Aβ16-21, which may be due to the formation of a more stable structures. This study offers valuable insights at the mechanistic level, which could prove beneficial in the development of new drugs to combat NDs.