BACTERIAL TOXIN INFORMATICS STUDY TO CHARACTERIZE THE UNDERLYING HUMAN PATHOLOGIES

Abstract

Neuroparalysis is induced by Clostridial botulinum neurotoxins (BoNTs) arresting synaptic exocytosis. BoNT comprises of three functional domains including translocation, protease and receptor binding. Its cleavage occurs into two disulfide linked polypeptide chains: a heayy chain (HC) translocon and a light chain (LC) protease. The BoNT intoxication process comprises of one of the most intriguing and elusive steps, i.e. the proteolytic light Chain translocation through the BoNT protein-conducting channel of the heavy Chain, from the endosomal compartment to the cytosol. The putative transporter proteins, synaptic vesicle glycoprotein 2 (SV2) family possesses 12 transmembrane domains associating with the receptor-binding luminal domain of the BoNTs. The aim of current study is to study the interaction pattern of BONT/A, D and E with luminal domain of SV2A, SV2B and SV2C receptors to explore them conserved binding clefts. Furthermore, through the information extracted from conserved residual contributions, we designed three peptides inhibitors (peptide-A. peptide-B and peptide-C) originated from the binding regions of SV2A. SV2B and SV2C receptors and tested their binding proficiencies against clostridial BONT/A, D and E. The Clostridial BONT/A exhibited more interactions with peptide-A, peptide-B and peptie-C as compared to Clostridial BONT/D and E. We additionally explored the stability as well as time-dependent behavior and dynamics of BoNT/A, D and E with peptide-C through 20 ns Molecular dynamics (MD) simulation assays. Our analysis indicated that BoNT/A attained more stability as compared to BoNT/D and E with peptide SV2C. Thus the proposed peptides inhibitors against the BoNT/A, D and E may serve as active therapeutic agents for the treatment of neurodegenerative disorders. Further studies are needed to test their therapeutic potential through in vitro and in vivo assays.