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Critical nucleus of Greek-key-like core of α-synuclein protofibril and its disruption by dopamine and norepinephrine

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Abstract

The formation of amyloid fibrils by α-synuclein (αS) protein inside the Lewy bodies and Lewy neurites is the prominent pathological hallmark of Parkinson's disease (PD). The fibrillation of αS in vitro is described by a nucleation–elongation process involving the formation of a critical nucleus. Finding the critical/smallest nuclei and effective inhibitors of αS aggregation is a crucial step for the development of drugs against PD. Recent experiments reported that dopamine (DA) and norepinephrine (NE), two prominent naturally occurring neurotransmitters, can effectively disrupt the preformed αS fibrils. The level of DA/NE in blood can be markedly increased by exercise. However, the size and structure of the critical nucleus and the disruptive mechanism by DA/NE are largely unknown. In this work, we performed multiple molecular dynamics (MD) simulations to find the critical nucleus size and examine the influences of DA/NE molecules on preformed αS44–96 (Greek-key-like core of full length αS) protofibrils. Our results show that the trimer is the critical nucleus for the αS44–96 fibril formation, and the tetramer is the minimal stable nucleus. When DA/NE molecules bind to the fibril-like trimer and tetramer, they strongly destabilize the αS protofibrils by disrupting the β-sheet structure and inter-chain E46-K80 salt bridges. Two common binding sites are identified for both DA and NE molecules on αS oligomers: residues 57–70 and 81–83. A different binding site is also observed, which is located at the N-terminal region (residues 45–52). The binding of DA/NE molecules to αS oligomers is mostly driven by hydrophobic and electrostatic interactions. We found two disruptive modes, and binding to the turn region of αS oligomers but disrupting the adjacent β-sheet structure is the dominant one. Our work identified the critical nucleus of Greek-key-like core of αS protofibrils and revealed the disruptive mechanism of αS protofibrils by DA/NE molecules, which may be helpful to the design of effective drugs against αS aggregation.

Graphical abstract: Critical nucleus of Greek-key-like core of α-synuclein protofibril and its disruption by dopamine and norepinephrine

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Publication details

The article was received on 20 Aug 2019, accepted on 17 Nov 2019 and first published on 18 Nov 2019


Article type: Paper
DOI: 10.1039/C9CP04610K
Phys. Chem. Chem. Phys., 2020, Advance Article

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    Critical nucleus of Greek-key-like core of α-synuclein protofibril and its disruption by dopamine and norepinephrine

    Y. Zou, Z. Qian, Y. Gong, Y. Tang, G. Wei and Q. Zhang, Phys. Chem. Chem. Phys., 2020, Advance Article , DOI: 10.1039/C9CP04610K

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