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Article

Structural Influence and Interactive Binding Behavior of Dopamine and Norepinephrine on the Greek-Key-Like Core of α-Synuclein Protofibril Revealed by Molecular Dynamics Simulations

by 1,†, 2,†, 2 and 2,*
1
Department of Sport and Exercise Science, College of Education, Zhejiang University, 148 Tianmushan Road, Hangzhou 310007, China
2
Key Laboratory of Exercise and Health Sciences (Ministry of Education) and School of Kinesiology, Shanghai University of Sport, 399 Changhai Road, Shanghai 200438, China
*
Author to whom correspondence should be addressed.
Y.Z. and Z.L. contributed equally to this work.
Processes 2019, 7(11), 850; https://doi.org/10.3390/pr7110850
Received: 10 August 2019 / Revised: 8 November 2019 / Accepted: 11 November 2019 / Published: 13 November 2019
(This article belongs to the Special Issue Molecular Dynamics Modeling and Simulation)
The pathogenesis of Parkinson’s disease (PD) is closely associated with the aggregation of α-synuclein (αS) protein. Finding the effective inhibitors of αS aggregation has been considered as the primary therapeutic strategy for PD. Recent studies reported that two neurotransmitters, dopamine (DA) and norepinephrine (NE), can effectively inhibit αS aggregation and disrupt the preformed αS fibrils. However, the atomistic details of αS-DA/NE interaction remain unclear. Here, using molecular dynamics simulations, we investigated the binding behavior of DA/NE molecules and their structural influence on αS44–96 (Greek-key-like core of full length αS) protofibrillar tetramer. Our results showed that DA/NE molecules destabilize αS protofibrillar tetramer by disrupting the β-sheet structure and destroying the intra- and inter-peptide E46–K80 salt bridges, and they can also destroy the inter-chain backbone hydrogen bonds. Three binding sites were identified for both DA and NE molecules interacting with αS tetramer: T54–T72, Q79–A85, and F94–K96, and NE molecules had a stronger binding capacity to these sites than DA. The binding of DA/NE molecules to αS tetramer is dominantly driven by electrostatic and hydrogen bonding interactions. Through aromatic π-stacking, DA and NE molecules can bind to αS protofibril interactively. Our work reveals the detailed disruptive mechanism of protofibrillar αS oligomer by DA/NE molecules, which is helpful for the development of drug candidates against PD. Given that exercise as a stressor can stimulate DA/NE secretion and elevated levels of DA/NE could delay the progress of PD, this work also enhances our understanding of the biological mechanism by which exercise prevents and alleviates PD. View Full-Text
Keywords: amyloid protofibril; small molecules; protein–ligand interaction; inhibitory mechanism; molecular dynamics simulation amyloid protofibril; small molecules; protein–ligand interaction; inhibitory mechanism; molecular dynamics simulation
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MDPI and ACS Style

Zou, Y.; Liu, Z.; Zhu, Z.; Qian, Z. Structural Influence and Interactive Binding Behavior of Dopamine and Norepinephrine on the Greek-Key-Like Core of α-Synuclein Protofibril Revealed by Molecular Dynamics Simulations. Processes 2019, 7, 850. https://doi.org/10.3390/pr7110850

AMA Style

Zou Y, Liu Z, Zhu Z, Qian Z. Structural Influence and Interactive Binding Behavior of Dopamine and Norepinephrine on the Greek-Key-Like Core of α-Synuclein Protofibril Revealed by Molecular Dynamics Simulations. Processes. 2019; 7(11):850. https://doi.org/10.3390/pr7110850

Chicago/Turabian Style

Zou, Yu, Zhiwei Liu, Zhiqiang Zhu, and Zhenyu Qian. 2019. "Structural Influence and Interactive Binding Behavior of Dopamine and Norepinephrine on the Greek-Key-Like Core of α-Synuclein Protofibril Revealed by Molecular Dynamics Simulations" Processes 7, no. 11: 850. https://doi.org/10.3390/pr7110850

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