In Silico Conformational Features of Botulinum Toxins A1 and E1 According to Intraluminal Acidification

Although botulinum neurotoxins (BoNTs) are among the most toxic compounds found in nature, their molecular mechanism of action is far from being elucidated. A key event is the conformational transition due to acidification of the interior of synaptic vesicles, leading to translocation of the BoNT catalytic domain into the neuronal cytosol. To investigate these conformational variations, homology modeling and atomistic simulations are combined to explore the internal dynamics of the sub-types BoNT/A1 (the most-used sub-type in medical applications) and BoNT/E1 (the most kinetically efficient sub-type). This first simulation study of di-chain BoNTs in closed and open states considers the effects of both neutral and acidic pH. The conformational mobility is driven by domain displacements of the ganglioside-binding site in the receptor binding domain, the translocation domain (HC [Formula: see text]) switch, and the belt [Formula: see text]-helix, which present multiple conformations, depending on the primary sequence and the pH. Fluctuations of the belt [Formula: see text]-helix are observed for closed conformations of the toxins and at acidic pH, while patches of more solvent-accessible residues appear under the same conditions in the core translocation domain HC [Formula: see text]. These findings suggest that, during translocation, the higher mobility of the belt could be transmitted to HC [Formula: see text] , leading to the favorable interaction of HC [Formula: see text] residues with the non-polar membrane environment.