In silico analysis of the conformational features of botulinic toxins A1 and E1
Résumé
Botulinum neurotoxins (BoNTs) are among the most powerful toxic compounds found in nature. They bind to pre-synaptic gangliosides and protein receptor complexes, which get internalized into recycling vesicles. Then, the inner acidification of vesicles induces a translocation of the catalytic domain into the cytosol, which next cleaves SNARE proteins to impair the action potential-mediated release of neurotransmitter into the neuromuscular cleft. The succession of these events is far from being elucidated at the atomic level, although numerous structures of the interaction partners have been determined. This is the reason for which we undertook a study of BoNTs by molecular dynamics simulations. Systems were prepared for the subtypes BoNT/A1 and BoNT/E1, with protonation levels defined by neutral and acidic pH values. The toxins flexibility is mainly described by the relative displacements of domains, variations of flexibility being observed in the ganglioside binding site in the domain HCC , the HN switch and the belt α helix. The belt α helix fluctuations are connected with the larger accessibility of residues in HN, allowing to propose a model for the translocation, in which the mobility of belt is transmitted to HN , inducing an easier interaction of HN residues with the non-polar membrane environment.
Domaines
Sciences du Vivant [q-bio]
Origine : Fichiers produits par l'(les) auteur(s)