Destabilisation of Alzheimer's amyloid-β protofibrils by Baicalein: mechanistic insights from all-atom molecular dynamics simulations

Alzheimer's disease (AD) is the most common form of dementia and the fifth leading cause of death globally. Aggregation and deposition of neurotoxic A beta fibrils in the neural tissues of the brain is a key hallmark in AD pathogenesis. Destabilisation studies of the amyloid-peptide by various natural molecules are highly relevant due to their neuroprotective and therapeutic potential for AD. We performed molecular dynamics (MD) simulation to investigate the destabilisation mechanism of amyloidogenic protofilament intermediate by Baicalein (BCL), a naturally occurring flavonoid. We found that the BCL molecule formed strong hydrophobic contacts with non-polar residues, specifically F19, A21, V24, and I32 of Chain A and B of the pentameric protofibril. Upon binding, it competed with the native hydrophobic contacts of the A beta protein. BCL loosened the tight packing of the hydrophobic core by disrupting the hydrogen bonds and the prominent D23-K28 inter-chain salt bridges of the protofibril. The decrease in the structural stability of A beta protofibrils was confirmed by the increased RMSD, radius of gyration, solvent accessible surface area (SASA), and reduced beta-sheet content. PCA indicated that the presence of the BCL molecule intensified protofibril motions, particularly affecting residues in Chain A and B regions. Our findings propose that BCL would be a potent destabiliser of A beta protofilament, and may be considered as a therapeutic agent in treating AD.Graphical abstractMolecular Docking, Molecular dynamics simulations were performed to analyse the destabilisation of Alzheimer's amyloid-beta protofibril (2BEG.pdb) by Baicalein.