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

Abstract

Fibrillary aggregates of amyloid-β (Aβ) are the pathological hallmark of Alzheimer’s disease (AD). Clearing Aβ deposition or inhibiting Aβ aggregation is a promising approach to treat AD. Experimental studies reported that dopamine (DA), an important neurotransmitter, can inhibit Aβ aggregation and disrupt Aβ fibrils in a dose-dependent manner. However, the underlying molecular mechanisms still remain mostly elusive. Herein, we investigated the effect of DA on Aβ42 protofibrils at three different DA-to-Aβ 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-Aβ ratio of 2:1 exhibits stronger Aβ 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-Aβ 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-Aβ ratio (10:1), a mixture of protonated (DA+) and deprotonated (DA0) DA molecules significantly disrupts Aβ protofibrils by the binding of DA0 to the F4-L34-V36 hydrophobic core. Replica-exchange molecular dynamics simulations of Aβ42 dimer show that DA+ inhibits the formation of β-sheets, K28-A42/K28-D23 salt-bridges, and interpeptide hydrophobic interactions and results in disordered coil-rich Aβ dimers, which would inhibit the subsequent fibrillization of Aβ. Further analyses reveal that DA disrupts Aβ protofibril and prevents Aβ dimerization mostly through π–π stacking interactions with residues F4, H6, and H13, hydrogen bonding interactions with negatively charged residues D7, E11, E22 and D23, and cation−π interactions with residues R5. This study provides a complete picture of the molecular mechanisms of DA in disrupting Aβ protofibril and inhibiting Aβ aggregation, which could be helpful for the design of potent drug candidates for the treatment/intervention of AD.

Cytotoxic Aβ Protofilaments Are Generated in the Process of Aβ Fibril Disaggregation

“…Considering that the decrease in the ThT fluorescence value from 0 to 6 h with the addition of 50 µM of DA ( Figure 2 A) was steeper than the decrease with the addition of 50 µM of EGCG ( Figure 1 A), the molecular mechanism for Aβ fibril disaggregation may be different between DA and EGCG. Recently, Wei and colleagues reported that both DA and EGCG disrupt the salt bridges between K28 and A42 by molecular dynamics (MD) simulations using the solved Aβ protofibril structure [ 17 , 27 ]. Additionally, MD simulations showed that DA bound to the hydrophobic site containing F4, L34, and V36 disrupts Aβ protofibrils, while EGCG breaks the H-bond between H6 and E11 of Aβ protofibrils [ 17 , 27 ].…”

“…Recently, Wei and colleagues reported that both DA and EGCG disrupt the salt bridges between K28 and A42 by molecular dynamics (MD) simulations using the solved Aβ protofibril structure [ 17 , 27 ]. Additionally, MD simulations showed that DA bound to the hydrophobic site containing F4, L34, and V36 disrupts Aβ protofibrils, while EGCG breaks the H-bond between H6 and E11 of Aβ protofibrils [ 17 , 27 ]. Similar to our results, the MD simulation studies indicate that the effects of DA and EGCG are different.…”

Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

“…On the one hand, DA can inhibit Aβ aggregation and disrupt Aβ fibrils in a dose-dependent manner ( Huong et al, 2010 ; Liu et al, 2016 ). Recently, Chen et al (2021) reported that DA disrupted Aβ protofibrils and prevented Aβ dimerization at the molecular level mostly through π-π stacking interactions with residues F4, H6, and H13; hydrogen-bonding interactions with negatively charged residues D7, E11, E22, and D23; and cation-π interactions with residue R5. This may be an important mechanism by which DA interferes with Aβ generation.…”

ALS-associated A315E and A315pT variants exhibit distinct mechanisms in inducing irreversible aggregation of TDP-43312–317 peptides

“…30,61,63 A salt bridge is considered to be formed when the minimum distance between the NH 3 + group in the main chain of a positively charged Nterminus and the COO À /HPO 3 À group in the side chain of a negatively charged/phosphorylated residue is less than 0.4 nm. [64][65][66][67] Two aromatic rings form p-p stacking interactions when their centroid distance is less than 0.7 nm. 67,68 In all of the statistical analyses, results are the average of the three individual MD trajectories of each system.…”