Destabilization of Alzheimers Amyloid-beta Protofibrils by Bai-calein: Mechanistic Insights from All-atom Molecular Dynamics Simulations

Alzheimer's disease (AD) is a neurodegenerative disorder; it is the most common form of de-mentia 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 the pathogenesis of AD. Desta-bilisation studies of the amyloid-peptide by various natural molecules are of the utmost rele-vance due to their enormous potential as neuroprotective and therapeutic agents for AD. We performed molecular dynamics (MD) simulation on the U-shaped pentamers of amyloidogenic protofilament intermediates to investigate the destabilisation mechanism in the presence of Bai-calein (BCL), a naturally occurring flavonoid. We found that the BCL molecule formed strong hydrophobic contacts with non-polar residues of the protofibril. Upon binding, it competed with the native hydrophobic contacts of the A-beta protein. BCL loosened the tight packing of the hydrophobic core of the protofibril by disrupting the inter-chain salt bridges and hydrogen bonds. The decrease in the structural stability of A-beta protofibrils was confirmed through the en-hanced root mean square deviation (RMSD), radius of gyration and solvent accessible surface area (SASA), and reduced beta-sheet content. PCA indicated that the presence of the BCL mole-cule 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.