{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:07:31Z","timestamp":1788872851600,"version":"build-2803163510"},"reference-count":74,"publisher":"American Chemical Society (ACS)","issue":"17","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mutations in the DNA methyltransferase 1 (DNMT1) enzyme can lead to neurodegenerative diseases, including autosomal dominant cerebellar ataxia\u2013deafness and neuropathy (ADCA-DN) and hereditary sensory and autonomic neuropathy type 1E (HSAN1E). The impact of these mutations on the structural dynamics of DNMT1 remains largely unknown. Here, we present an extensive molecular dynamics investigation of wild-type (WT) DNMT1 and its mutants associated with ADCA-DN (A554V, G589A, and V590F) and HSAN1E (D490E-P491Y and Y495C). The first group of mutants increases structural flexibility and disrupts the allosteric communication relative to WT DNMT1. These findings provide a molecular explanation for the reduced in vitro thermostability observed in these mutants. The second group has a similar impact on structural flexibility and allosteric communication and increases solvent exposure at mutant sites, offering a plausible structural explanation for the experimentally observed aberrant protein degradation and cleavage. Furthermore, all the investigated variants alter the most significant large-scale motions of the enzyme. This disruption of motion, together with decreased structural stability, may affect DNMT1\u2019s molecular recognition processes with its cellular partners. Overall, this study sheds light on the molecular mechanisms underlying ADCA-DN and HSAN1E, which could inform the development of therapies.<\/jats:p>","DOI":"10.1021\/acs.jctc.6c00982","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T13:02:21Z","timestamp":1787403741000},"page":"9179-9187","source":"Crossref","is-referenced-by-count":0,"title":["Disease-Associated\nMutations Impact DNA Methyltransferase\n1 Function through Dynamic Allosteric Effects and Solvent Exposure"],"prefix":"10.1021","volume":"22","author":[{"given":"Song","family":"Xie","sequence":"first","affiliation":[{"name":"Institute of Neuroscience and Medicine (INM-9) Computational Biomedicine , Forschungszentrum Ju\u0308lich GmbH , ,","place":["Ju\u0308lich, Germany, 52428"]},{"name":"RWTH Aachen University , , ,","place":["Aachen, Germany, 52074"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can Bora","family":"Yildiz","sequence":"additional","affiliation":[{"name":"RWTH Aachen University , , Worringerweg 3 , ,","place":["Aachen, Germany, 52074"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Ruggerone","sequence":"additional","affiliation":[{"name":"University of Cagliari , , Cittadella Universitaria, S.P.monserrato-Sestu Km 0.700 , ,","place":["Monserrato (CA), Italy, I-09044"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zuo","sequence":"additional","affiliation":[{"name":"Chongqing University of Arts and Sciences , , ,","place":["Chongqing, PR China, 402160"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine","family":"Zimmer-Bensch","sequence":"additional","affiliation":[{"name":"RWTH Aachen University , , Worringerweg 3 , ,","place":["Aachen, Germany, 52074"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9010-0149","authenticated-orcid":true,"given":"Paolo","family":"Carloni","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and Medicine (INM-9) Computational Biomedicine , Forschungszentrum Ju\u0308lich GmbH , ,","place":["Ju\u0308lich, Germany, 52428"]},{"name":"RWTH Aachen University , , ,","place":["Aachen, Germany, 52074"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"issue":"1","key":"2026090808093877900_cit1","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA Methylation and Its Basic Function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"issue":"1","key":"2026090808093877900_cit2","doi-asserted-by":"publisher","first-page":"6834","DOI":"10.1038\/s41467-025-62114-0","article-title":"DNMT1-mediated regulation of somatostatin-positive\ninterneuron migration impacts cortical architecture and function","volume":"16","author":"Reichard","year":"2025","journal-title":"Nat. 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Genet"},{"issue":"36","key":"2026090808093877900_cit17","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abe8511","article-title":"Mutation-induced\nDNMT1 cleavage drives neurodegenerative disease","volume":"7","author":"Wang","year":"2021","journal-title":"Sci. Adv."},{"issue":"3","key":"2026090808093877900_cit18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002433","article-title":"Corresponding Functional\nDynamics across the Hsp90 Chaperone Family: Insights from a Multiscale\nAnalysis of MD Simulations","volume":"8","author":"Morra","year":"2012","journal-title":"PLoS Comput. 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A."},{"issue":"6020","key":"2026090808093877900_cit21","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1126\/science.1195380","article-title":"Structure\nof DNMT1-DNA\nComplex Reveals a Role for Autoinhibition in Maintenance DNA Methylation","volume":"331","author":"Song","year":"2011","journal-title":"Science"},{"issue":"6069","key":"2026090808093877900_cit22","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1126\/science.1214453","article-title":"Structure-Based\nMechanistic Insights into DNMT1-Mediated Maintenance DNA Methylation","volume":"335","author":"Song","year":"2012","journal-title":"Science"},{"issue":"1","key":"2026090808093877900_cit23","doi-asserted-by":"publisher","first-page":"7023","DOI":"10.1038\/ncomms8023","article-title":"Molecular mechanism\nfor USP7-mediated DNMT1 stabilization by acetylation","volume":"6","author":"Cheng","year":"2015","journal-title":"Nat. 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Theory Comput."},{"issue":"45","key":"2026090808093877900_cit34","doi-asserted-by":"publisher","first-page":"11623","DOI":"10.1021\/j100096a001","article-title":"Ab Initio Calculation\nof Vibrational Absorption and Circular Dichroism Spectra Using Density\nFunctional Force Fields","volume":"98","author":"Stephens","year":"1994","journal-title":"J. Phys. Chem."},{"issue":"4","key":"2026090808093877900_cit35","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1063\/1.476673","article-title":"6-31G* basis set\nfor atoms K through Zn","volume":"109","author":"Rassolov","year":"1998","journal-title":"J. Chem. Phys."},{"issue":"40","key":"2026090808093877900_cit36","doi-asserted-by":"publisher","first-page":"10269","DOI":"10.1021\/j100142a004","article-title":"A well-behaved electrostatic\npotential based method using charge restraints for deriving atomic\ncharges: the RESP model","volume":"97","author":"Bayly","year":"1993","journal-title":"J. Phys. 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Biol."},{"key":"2026090808093877900_cit59","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.sbi.2018.09.004","article-title":"Modulation\nof allosteric coupling by mutations: from protein dynamics and packing\nto altered native ensembles and function","volume":"54","author":"Naganathan","year":"2019","journal-title":"Curr.\nOpin. Struct. Biol."},{"issue":"1","key":"2026090808093877900_cit60","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1110\/ps.0225803","article-title":"Protein\nhydrogen exchange mechanism: Local fluctuations","volume":"12","author":"Maity","year":"2003","journal-title":"Protein Sci."},{"issue":"37","key":"2026090808093877900_cit61","doi-asserted-by":"publisher","first-page":"16096","DOI":"10.1073\/pnas.1004213107","article-title":"Charges\nin the hydrophobic interior of proteins","volume":"107","author":"Isom","year":"2010","journal-title":"Proc.\nNatl. Acad. Sci. U. S. 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