A Comprehensive Insight into the Mechanisms of Dopamine in Disrupting Aβ Protofibrils and Inhibiting Aβ Aggregation

Fibrillary aggregates of amyloid-beta (A beta) are the pathological hallmark of Alzheimer's disease (AD). Clearing A beta deposition or inhibiting A beta aggregation is a promising approach to treat AD. Experimental studies reported that dopamine (DA), an important neurotransmitter, can inhibit A beta aggregation and disrupt A beta fibrils in a dose-dependent manner. However, the underlying molecular mechanisms still remain mostly elusive. Herein, we investigated the effect of DA on A beta(42) protofibrils at three different DA-to-A beta molar ratios (1:1, 2:1, and 10:1) using all-atom molecular dynamics simulations. Our simulations demonstrate that protonated DA at a DA-to-A beta ratio of 2:1 exhibits stronger A beta protofibril disruptive capacity than that at a molar-ratio of 1:1 by mostly disrupting the F4-L34-V36 hydrophobic core. When the ratio of DA-to-A beta increases to 10:1, DA has a high probability to bind to the outer surface of protofibril and has negligible effect on the protofibril structure. Interestingly, at the same DA-to-A beta ratio (10:1), a mixture of protonated (DA(+)) and deprotonated (DA(0)) DA molecules significantly disrupts A beta protofibrils by the binding of DA(0) to the F4-L34-V36 hydrophobic core. Replica-exchange molecular dynamics simulations of A beta(42) dimer show that DA(+) inhibits the formation of beta-sheets, K28-A42/K28-D23 salt-bridges, and interpeptide hydrophobic interactions and results in disordered coil-rich A beta dimers, which would inhibit the subsequent fibrillization of A beta. Further analyses reveal that DA disrupts A beta protofibril and prevents A beta dimerization mostly through pi-pi stacking interactions with residues F4, H6, and H13, hydrogen bonding interactions with negatively charged residues D7, E11, E22 and D23, and cation-pi interactions with residues R5. This study provides a complete picture of the molecular mechanisms of DA in disrupting A beta protofibril and inhibiting A beta aggregation, which could be helpful for the design of potent drug candidates for the treatment/intervention of AD.