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

Abstract

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

Keywords:

• Parkinson’s disorder
• alpha-synuclein
• aggregation
• therapeutic peptides
• beta-sheet breaker
• DMD

Acknowledgements

The authors gratefully acknowledge the Indian Council of Medical Research (ICMR), the Government of India agency, for the research grant (File no:5/4–5/Neuro/226/2020/NCD-I). Also, the authors thank VIT for providing infrastructure for carrying out this research work. In particular, we thank VIT Centre for Technical Support for providing NVIDIA DGX 1 computational resources to carry out molecular simulations.

Disclosure statement

No potential conflict of interest was reported by the authors.