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Mechanistic Insight into the Binding Profile of DCVJ and alpha-Synuclein Fibril Revealed by Multiscale Simulations
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-3138-820X
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0003-0185-5724
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. College of Chemistry and Chemical Engineering, Henan University, Kaifeng, Henan, 475004P. R. China.ORCID iD: 0000-0002-1763-9383
2019 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 10, no 1, p. 610-617Article in journal (Refereed) Published
Abstract [en]

Parkinson's disease (PD) is a serious neuro-degenerative disease and is characterized by abnormal alpha-synuclein (alpha-syn) accumulation in Lewy bodies (LB) and 2 Lewy neurites (LN), which makes alpha-syn an important imaging target for PD. An imaging probe that quantifies fibrillar alpha-syn can enhance the clinical diagnosis of PD and can also be used to evaluate the efficacy of therapeutics aimed at reducing the abnormal aggregation of the alpha-syn fibril in the brain. In this paper, we study the binding profile of fibrillar alpha-syn with a fluorescent probe 4-(dicyanovinyl)julolidine (DCVJ), which is being explored for identifying alpha-syn imaging agents. A multiscale simulation workflow including molecular docking, molecular dynamics, metadynamics, and QM/MM calculations was implemented. We find that DCVJ can bind to multiple sites of alpha-syn which are located either at the surface or in the core. Free energy calculations using implicit solvent models reveal that the most favorable binding mode for DCVJ is associated with the core binding site and is further confirmed by metadyamics simulation. Besides, a dynamic binding pathway is discovered, which reveals that DCVJ binds gradually into the core of the fibril passing through several intermediate states. The conformational arrest of the dicyano vinyl group in the fibrillar environment could explain the reason behind the fibril-specific fluorescence of DCVJ. Furthermore, based on hybrid QM/MM calculations, the molecular geometry of the dicyano vinyl group is found to be environment specific which explains why DCVJ serves as a staining agent for such fibrillar-like environments. Our results could be helpful for elucidating the binding mechanism of imaging tracers with the fibrillar form of alpha-syn and explain their fibrillar-specific optical properties, a knowledge that in turn can be used to guide the design and development of compounds with higher affinity and selectivity for alpha-syn using structure-based strategies.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2019. Vol. 10, no 1, p. 610-617
Keywords [en]
alpha-Synuclein, DCVJ, imaging agents, molecular docking, binding free energy calculations, metadynamics
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-243968DOI: 10.1021/acschemneuro.8b00465ISI: 000456351300062PubMedID: 30277753Scopus ID: 2-s2.0-85055257565OAI: oai:DiVA.org:kth-243968DiVA, id: diva2:1293009
Note

QC 20190301

Available from: 2019-03-01 Created: 2019-03-01 Last updated: 2019-03-01Bibliographically approved

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Guanglin, KuangMurugan, Natarajan ArulÅgren, Hans

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