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J Mol Graph Model. 2017 Jun;74:288-295. doi: 10.1016/j.jmgm.2017.04.019. Epub 2017 Apr 20.

Probing the inhibitory activity of epigallocatechin-gallate on toxic aggregates of mutant (L84F) SOD1 protein through geometry based sampling and steered molecular dynamics.

Author information

1
Bioinformatics Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
2
Bioinformatics Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India. Electronic address: rrajasekaran@vit.ac.in.

Abstract

Amyloid formation and protein aggregation are considered to be at the core of the disease pathology for the various neurodegenerative disorders such as Amyotrophic lateral sclerosis (ALS). Considerable experimental reports have suggested that epigallocatechin-gallate (EGCG), a natural polyphenol from the green tea inhibits the amyloid formation in multiple neurodegenerative disease. Mutations in SOD1 protein are considered to a key factor that contributes towards the rapid disease progression and the pathogenesis in both, the sporadic and familial form. In our study, we computationally examined the inhibitory action of EGCG against the native and the mutant SOD1 through molecular docking, steered molecular dynamics and conformational sampling methods From the outcome, we could conjecture that the protein destabilization and increased β-sheet propensity that occurred due to mutation were regained upon the binding of EGCG. Moreover, the concepts of the free energy landscape analysis are introduced to establish the visual appearance of protein aggregation upon mutation. Altogether, we come to know that the binding of EGCG on mutant SOD1 has reduced the formation of the toxic aggregates upon mutation. Hence, our study could be an initiative in deciphering the inhibitory action of EGCG against the aggregated mutant SOD1, which could be a therapeutic potential against the treatment for the incurable neurodegenerative disorder (ALS) affecting the mankind.

KEYWORDS:

Conformational sampling; Docking; EGCG; L84F; SOD1

PMID:
28458007
DOI:
10.1016/j.jmgm.2017.04.019
[Indexed for MEDLINE]

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