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Computer aided therapeutic tripeptide design, in alleviating the pathogenic proclivities of nocuous α-synuclein fibrils

Chandrasekhar, G and Srinivasan, E and Nandhini, S and Pravallika, G and Sanjay, G and Rajasekaran, R (2023) Computer aided therapeutic tripeptide design, in alleviating the pathogenic proclivities of nocuous α-synuclein fibrils. In: Journal of Biomolecular Structure and Dynamics .

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Official URL: https://doi.org/10.1080/07391102.2023.2194003


Parkinson’s disorder (PD) exacerbates neuronal degeneration of motor nerves, thereby effectuating uncoordinated movements and tremors. Aberrant alpha-synuclein (α-syn) is culpable of triggering PD, wherein cytotoxic amyloid aggregates of α-syn get deposited in motor neurons to instigate neuro-degeneration. Amyloid aggregates, typically rich in beta sheets are cardinal targets to mitigate their neurotoxic effects. In this analysis, owing to their interaction specificity, we formulated an efficacious tripeptide out of the aggregation-prone region of α-syn protein. With the help of a proficient computational pipeline, systematic peptide shortening and an adept molecular simulation platform, we formulated a tripeptide, VAV from α-syn structure based hexapeptide KISVRV. Indeed, the VAV tripeptide was able to effectively mitigate the α-syn amyloid fibrils’ dynamic rate of beta-sheet formation. Additional trajectory analyses of the VAV- α-syn complex indicated that, upon its dynamic interaction, VAV efficiently altered the distinct pathogenic structural dynamics of α-syn, further advocating its potential in alleviating aberrant α-syn’s amyloidogenic proclivities. Consistent findings from various computational analyses have led us to surmise that VAV could potentially re-alter the pathogenic conformational orientation of α-syn, essential to mitigate its cytotoxicity. Hence, VAV tripeptide could be an efficacious therapeutic candidate to efficiently ameliorate aberrant α-syn amyloid mediated neurotoxicity, eventually attenuating the nocuous effects of PD. Communicated by Ramaswamy H. Sarma.

Item Type: Journal Article
Publication: Journal of Biomolecular Structure and Dynamics
Publisher: Taylor and Francis Ltd.
Additional Information: The copyright for this article belongs to Taylor and Francis Ltd.
Keywords: aggregation; alpha-synuclein; beta-sheet breaker; DMD; Parkinson’s disorder; therapeutic peptides
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 18 Apr 2023 10:29
Last Modified: 18 Apr 2023 10:29
URI: https://eprints.iisc.ac.in/id/eprint/81341

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