{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:45:10Z","timestamp":1792784710165,"version":"4.5.0"},"reference-count":34,"publisher":"American Chemical Society (ACS)","issue":"37","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"name":"Natural Science Research Project of Anhui Educational Committee","award":["2024AH050982"],"award-info":[{"award-number":["2024AH050982"]}]},{"name":"Clinical Research Project of Anhui University of Chinese Medicine","award":["2024YFYLCZX23"],"award-info":[{"award-number":["2024YFYLCZX23"]}],"id":[{"id":"https:\/\/ror.org\/02my3bx32","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Wilson disease (WD) is a severe metabolic disorder caused by mutations in the copper-transporting ATPase ATP7B. The MBD5\u20136 tandem module serves as a critical regulatory hub for the protein, harboring several pathogenic missense mutations, including T587M, A595T, and R616Q within the MBD6 domain. However, the atomistic mechanisms by which these localized defects propagate across the MBD5\u20136 tandem module to disrupt interdomain organization remain unclear. In this study, we employed AlphaFold 3 to generate initial structures of the wild-type and variant ATP7B, followed by three independent 500 ns all-atom molecular dynamics (MD) simulations of the extracted apo MBD5\u20136 region. Our results reveal that these pathogenic mutations disrupt module-level structural stability through distinct microscopic physicochemical mechanisms. Specifically, T587 M triggers steric overpacking and abnormal rigidification; A595T induces hydrophobic core melting and water penetration; and R616Q abolishes critical electrostatic tethers. Crucially, we uncover a multiscale pathogenic mechanism, in which localized perturbations propagate via the flexible linker, allosterically disrupting the interdomain structural tethering to drive macroscopic conformational heterogeneity. This study delineates a multiscale pathway from local atomic defects to interdomain dysfunction within the apo MBD5\u20136 module and provides structural hypotheses for how these perturbations may affect the conformational regulation of full-length ATP7B.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c02764","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:02:02Z","timestamp":1788886922000},"page":"9379-9388","source":"Crossref","is-referenced-by-count":0,"title":["Atomistic Mechanisms of Allosteric Dysfunction in\nWilson Disease: How Local ATP7B Mutations Propagate to Global Destabilization"],"prefix":"10.1021","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5871-9274","authenticated-orcid":true,"given":"Moujun","family":"Luan","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Anhui University of Chinese Medicine , , , ,","place":["Hefei, Anhui, China, 230031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangli","family":"Cheng","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Anhui University of Chinese Medicine , , , ,","place":["Hefei, Anhui, China, 230031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Cao","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Anhui University of Chinese Medicine , , , ,","place":["Hefei, Anhui, China, 230031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Yao","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Anhui Medical University North District, Anhui Public Health Clinical Center , , ,","place":["Hefei, Anhui, China, 230012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Anhui University of Chinese Medicine , , , ,","place":["Hefei, Anhui, China, 230031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxing","family":"Huo","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Anhui University of Chinese Medicine , , , ,","place":["Hefei, Anhui, China, 230031"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"issue":"4","key":"2026091708470947400_cit1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25042402","article-title":"Epidemiology of\nWilson\u2019s disease and pathogenic variants of the ATP7B gene\nleading to diversified protein disfunctions","volume":"25","author":"Ovchinnikova","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"2026091708470947400_cit2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2025.1673283","article-title":"The role of copper dysregulation in Wilson disease:\nan expert opinion","volume":"12","author":"Stremmel","year":"2025","journal-title":"Front. Med."},{"key":"2026091708470947400_cit3","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2026.1766223","article-title":"Multiscale computational\ngenomics in Wilson disease: from atomic dynamics to clinical prediction","volume":"17","author":"Luan","year":"2026","journal-title":"Front. Genet."},{"issue":"21","key":"2026091708470947400_cit4","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics15212689","article-title":"Evaluation\nof the Relationship Between Neurologic Manifestations and Genetic\nMutations in Wilson\u2019s Disease with Next-Generation Sequencing","volume":"15","author":"Akbulut","year":"2025","journal-title":"Diagnostics"},{"issue":"1","key":"2026091708470947400_cit5","doi-asserted-by":"publisher","DOI":"10.1155\/humu\/8416660","article-title":"Analyses of ATP7B mRNA\nin Nasopharyngeal Swab Samples Increase Yields of Wilson Disease Molecular\nGenetic Diagnostics","volume":"2026","author":"Mra\u0301zova\u0301","year":"2026","journal-title":"Hum. Mutat."},{"issue":"6","key":"2026091708470947400_cit6","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1007\/s10534-017-0058-2","article-title":"The six metal\nbinding domains in\nhuman copper transporter, ATP7B: molecular biophysics and disease-causing\nmutations","volume":"30","author":"Ario\u0308z","year":"2017","journal-title":"BioMetals"},{"issue":"12","key":"2026091708470947400_cit7","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12122833","article-title":"Spectrum of Pathogenic\nVariants of the ATP7B Gene and\nGenotype\u2013Phenotype Correlation in Eastern Eurasian Patient\nCohorts with Wilson\u2019s Disease","volume":"12","author":"Garbuz","year":"2024","journal-title":"Biomedicines"},{"issue":"1","key":"2026091708470947400_cit8","doi-asserted-by":"publisher","DOI":"10.1155\/humu\/7485658","article-title":"Functional screen of wilson disease\nATP7B variants reveals residual transport activities","volume":"2025","author":"Calvo","year":"2025","journal-title":"Hum. Mutat."},{"issue":"9","key":"2026091708470947400_cit9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1010074","article-title":"Copper binding\nleads to increased dynamics in the regulatory N-terminal domain of\nfull-length human copper transporter ATP7B","volume":"18","author":"Ora\u0308dd","year":"2022","journal-title":"PLOS Comput. Biol."},{"issue":"5","key":"2026091708470947400_cit10","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112417","article-title":"Structures\nof the human Wilson disease copper transporter ATP7B","volume":"42","author":"Yang","year":"2023","journal-title":"Cell Rep."},{"issue":"5","key":"2026091708470947400_cit11","doi-asserted-by":"publisher","first-page":"638","DOI":"10.7150\/thno.14596","article-title":"Spectrum and Classification of ATP7B\nVariants in a Large Cohort of\nChinese Patients with Wilson\u2019s Disease Guides Genetic Diagnosis","volume":"6","author":"Dong","year":"2016","journal-title":"Theranostics"},{"issue":"1","key":"2026091708470947400_cit12","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.parkreldis.2013.09.021","article-title":"Genetic defects in\nIndian Wilson disease patients and genotype-phenotype correlation","volume":"20","author":"Mukherjee","year":"2014","journal-title":"Parkinsonism Relat. Disord."},{"issue":"2","key":"2026091708470947400_cit13","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1089\/109065703322146786","article-title":"Characterization of\nthe molecular defect in the ATP7B gene in Wilson disease patients\nfrom Yugoslavia","volume":"7","author":"Loudianos","year":"2003","journal-title":"Genet. Test."},{"issue":"4","key":"2026091708470947400_cit14","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaf340","article-title":"Beyond static structures:\nprotein dynamic conformations modeling\nin the post-AlphaFold era","volume":"26","author":"Cui","year":"2025","journal-title":"Briefings Bioinf."},{"issue":"4","key":"2026091708470947400_cit15","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1039\/D4CB00282B","article-title":"Decoding allosteric\nlandscapes: computational methodologies for enzyme modulation and\ndrug discovery","volume":"6","author":"Zhu","year":"2025","journal-title":"RSC Chem. Biol."},{"issue":"1","key":"2026091708470947400_cit16","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s10534-016-9976-7","article-title":"Disease-causing\npoint-mutations in metal-binding domains\nof Wilson disease protein decrease stability and increase structural\ndynamics","volume":"30","author":"Kumar","year":"2017","journal-title":"BioMetals"},{"issue":"2","key":"2026091708470947400_cit17","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1111\/cge.14352","article-title":"Functional\ncharacterization\nof novel or yet uncharacterized ATP7B missense variants detected in\npatients with clinical Wilson\u2019s disease","volume":"104","author":"Stalke","year":"2023","journal-title":"Clin. Genet."},{"issue":"10","key":"2026091708470947400_cit18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026245","article-title":"Elucidation\nof the ATP7B N-domain Mg2+-ATP coordination site and its allosteric\nregulation","volume":"6","author":"Hercend","year":"2011","journal-title":"PLoS One"},{"issue":"6","key":"2026091708470947400_cit19","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1007\/s10534-019-00219-y","article-title":"Wilson disease\nmissense mutations in ATP7B affect metal-binding domain structural\ndynamics","volume":"32","author":"Shanmugavel","year":"2019","journal-title":"BioMetals"},{"issue":"8016","key":"2026091708470947400_cit20","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure\nprediction of\nbiomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"2026091708470947400_cit21","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance\nmolecular simulations through multi-level parallelism from laptops\nto supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"issue":"9","key":"2026091708470947400_cit22","doi-asserted-by":"publisher","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the additive CHARMM\nall-atom protein force field targeting improved sampling of the backbone\n\u03d5, \u03c8 and side-chain \u03c71 and \u03c72 dihedral angles","volume":"8","author":"Best","year":"2012","journal-title":"J. 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Chem.\nPhys."},{"issue":"12","key":"2026091708470947400_cit28","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1002\/bip.360221211","article-title":"Dictionary of protein secondary structure: pattern\nrecognition of hydrogen-bonded and geometrical features","volume":"22","author":"Kabsch","year":"1983","journal-title":"Biopolymers"},{"issue":"1","key":"2026091708470947400_cit29","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: visual\nmolecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graphics"},{"issue":"29","key":"2026091708470947400_cit30","doi-asserted-by":"publisher","first-page":"10550","DOI":"10.1073\/pnas.1402768111","article-title":"Energy landscape views for interplays\namong folding, binding, and allostery of calmodulin domains","volume":"111","author":"Li","year":"2014","journal-title":"Proc. Natl. Acad. Sci. 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U.S.A."},{"issue":"10","key":"2026091708470947400_cit34","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1021\/acs.biochem.6b01152","article-title":"Electrostatic interactions as mediators\nin the allosteric activation of protein kinase A RI\u03b1","volume":"56","author":"Barros","year":"2017","journal-title":"Biochemistry"}],"container-title":["The Journal of Physical Chemistry B"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jpcb.6c02764","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article-pdf\/130\/37\/9379\/68451440\/acs.jpcb.6c02764.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article-pdf\/130\/37\/9379\/68451440\/acs.jpcb.6c02764.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:04:18Z","timestamp":1789653858000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article\/130\/37\/9379\/5426541\/Atomistic-Mechanisms-of-Allosteric-Dysfunction-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":34,"journal-issue":{"issue":"37","published-online":{"date-parts":[[2026,9,8]]},"published-print":{"date-parts":[[2026,9,17]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jpcb.6c02764","relation":{},"ISSN":["1520-6106","1520-5207"],"issn-type":[{"value":"1520-6106","type":"print"},{"value":"1520-5207","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]}}}