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

Parkinson's disorder (PD) exacerbates neuronal degeneration of motor nerves, thereby effectuating uncoordinated movements and tremors. Aberrant alpha-synuclein (alpha-syn) is culpable of triggering PD, wherein cytotoxic amyloid aggregates of alpha-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 alpha-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 alpha-syn structure based hexapeptide KISVRV. Indeed, the VAV tripeptide was able to effectively mitigate the alpha-syn amyloid fibrils' dynamic rate of beta-sheet formation. Additional trajectory analyses of the VAV- alpha-syn complex indicated that, upon its dynamic interaction, VAV efficiently altered the distinct pathogenic structural dynamics of alpha-syn, further advocating its potential in alleviating aberrant alpha-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 alpha-syn, essential to mitigate its cytotoxicity. Hence, VAV tripeptide could be an efficacious therapeutic candidate to efficiently ameliorate aberrant alpha-syn amyloid mediated neurotoxicity, eventually attenuating the nocuous effects of PD.Communicated by Ramaswamy H. Sarma