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Computational Study on the Role of γ-Synuclein in Inhibiting the α-Synuclein Aggregation

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Background: α-Synuclein (αS) is the precursor protein present in Lewy Bodies that helps in the formation of highly ordered amyloid fibrils that is associated with the occurrence of Parkinson’s disease, a neuro-degenerative disorder. Many reports have now been focused on finding the probable targets to weaken this debilitating disease. Recently γ-synuclein (γS), a presynaptic protein, was highlighted to inhibit the aggregation propensity of αS both in vivo and in vitro. However the nature, location and specificity of molecular interactions existing between the αS and γS is not known in spite of the potential importance of γS as an inhibitor of αS.

Objective: To understand the inhibition of αS aggregation by γS at the molecular level.

Methods: Umbrella sampling method was used along with molecular dynamics simulation to investigate the conformational dynamics, degree of association and molecular interaction between the monomeric units in the αS/γS hetero-dimer.

Results and Discussion: The dissociation energy barrier for αS/γS hetero-dimer was found to be higher than αS/αS homo-dimer. αS can therefore readily form a hetero-dimer by combining with γS than forming a homo-dimer. We also observed strong transient interactions involving hydrogen bonds, salt-bridges and non-bonded contacts between the monomeric units in αS/γS hetero-dimer.

Conclusion: Our findings suggest that γS may inhibit the aggregation propensity of αS.
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Keywords: Lewy bodies; homo-dimer; molecular dynamics; parkinson's disease; potential of mean force; self-assembly

Document Type: Research Article

Publication date: April 1, 2019

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  • Central Nervous System Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new central nervous system agents. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics in central nervous system medicinal chemistry.

    Central Nervous System Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in central nervous system drug discovery.
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