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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 (HCNT) switch, and the belt \u03b1-helix, which present multiple conformations, depending on the primary sequence and the pH. Fluctuations of the belt \u03b1-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 HCNT. These findings suggest that, during translocation, the higher mobility of the belt could be transmitted to HCNT, leading to the favorable interaction of HCNT residues with the non-polar membrane environment.<\/jats:p>","DOI":"10.3390\/toxins14090644","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T04:28:55Z","timestamp":1663648135000},"page":"644","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["In Silico Conformational Features of Botulinum Toxins A1 and E1 According to Intraluminal Acidification"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6923-6394","authenticated-orcid":false,"given":"Grazia","family":"Cottone","sequence":"first","affiliation":[{"name":"Department of Physics and Chemistry Emilio Segr\u00e9, University of Palermo, Viale delle Scienze, 90128 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8278-7075","authenticated-orcid":false,"given":"Letizia","family":"Chiodo","sequence":"additional","affiliation":[{"name":"Department of Engineering, University Campus Bio-Medico of Rome, Via \u00c1. del Portillo 21, 00128 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Maragliano","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy"},{"name":"Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9305-8989","authenticated-orcid":false,"given":"Michel-Robert","family":"Popoff","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR6047, Inserm U1306, Unit\u00e9 des Toxines Bact\u00e9riennes, 75015 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Rasetti-Escargueil","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR6047, Inserm U1306, Unit\u00e9 des Toxines Bact\u00e9riennes, 75015 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9080-7761","authenticated-orcid":false,"given":"Emmanuel","family":"Lemichez","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR6047, Inserm U1306, Unit\u00e9 des Toxines Bact\u00e9riennes, 75015 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3276-3366","authenticated-orcid":false,"given":"Th\u00e9r\u00e8se E.","family":"Malliavin","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR3528, Unit\u00e9 de Bioinformatique Structurale, 75015 Paris, France"},{"name":"Laboratoire de Physique et Chimie Th\u00e9oriques (LPCT), CNRS UMR7019, University of Lorraine, 54506 Vandoeuvre-l\u00e8s-Nancy, France"},{"name":"Laboratoire International Associ\u00e9, CNRS and University of Illinois at Urbana-Champaign, 54506 Vandoeuvre-l\u00e8s-Nancy, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1146\/annurev-biochem-013118-111654","article-title":"Botulinum and Tetanus Neurotoxins","volume":"88","author":"Dong","year":"2019","journal-title":"Annu. 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