{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T04:11:49Z","timestamp":1776312709905,"version":"3.50.1"},"reference-count":117,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T00:00:00Z","timestamp":1653264000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/R002363\/1"],"award-info":[{"award-number":["BB\/R002363\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2022,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ferritins are ubiquitous diiron enzymes involved in iron(II) detoxification and oxidative stress responses and can act as metabolic iron stores. The overall reaction mechanisms of ferritin enzymes are still unclear, particularly concerning the role of the conserved, near catalytic center Tyr residue. Thus, we carried out a computational study of a ferritin using a large cluster model of well over 300 atoms including its first\u2010 and second\u2010coordination sphere. The calculations reveal important insight into the structure and reactivity of ferritins. Specifically, the active site Tyr residue delivers a proton and electron in the catalytic cycle prior to iron(II) oxidation. In addition, the calculations highlight a likely cation binding site at Asp<jats:sub>65<\/jats:sub>, which through long\u2010range electrostatic interactions, influences the electronic configuration and charge distributions of the metal center. The results are consistent with experimental observations but reveal novel detail of early mechanistic steps that lead to an unusual mixed\u2010valent iron(III)\u2010iron(II) center.<\/jats:p>","DOI":"10.1002\/cbic.202200257","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T08:05:00Z","timestamp":1651737900000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Second Coordination Sphere Effects on the Mechanistic Pathways for Dioxygen Activation by a Ferritin: Involvement of a Tyr Radical and the Identification of a Cation Binding Site"],"prefix":"10.1002","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9302-6194","authenticated-orcid":false,"given":"Chieh\u2010Chih George","family":"Yeh","sequence":"first","affiliation":[{"name":"Manchester Institute of Biotechnology The University of Manchester  131 Princess Street Manchester M1 7DN UK"},{"name":"Department of Chemical Engineering The University of Manchester  Oxford Road Manchester M13 9PL UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0361-4556","authenticated-orcid":false,"given":"Thirakorn","family":"Mokkawes","sequence":"additional","affiliation":[{"name":"Manchester Institute of Biotechnology The University of Manchester  131 Princess Street Manchester M1 7DN UK"},{"name":"Department of Chemical Engineering The University of Manchester  Oxford Road Manchester M13 9PL UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1635-4455","authenticated-orcid":false,"given":"Justin M.","family":"Bradley","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Structural Biochemistry School of Chemistry University of East Anglia  Norwich NR4 7TJ UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9780-4061","authenticated-orcid":false,"given":"Nick E.","family":"Le Brun","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Structural Biochemistry School of Chemistry University of East Anglia  Norwich NR4 7TJ UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2620-8788","authenticated-orcid":false,"given":"Sam P.","family":"de Visser","sequence":"additional","affiliation":[{"name":"Manchester Institute of Biotechnology The University of Manchester  131 Princess Street Manchester M1 7DN UK"},{"name":"Department of Chemical Engineering The University of Manchester  Oxford Road Manchester M13 9PL UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,5,23]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"\u00a0"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr9500500"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr020443g"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr0307143"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/b139087"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.1039\/B604190F"},{"key":"e_1_2_8_7_2","volume-title":"Handbook of Porphyrin Science","author":"Kadish K. M.","year":"2010"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1193478"},{"key":"e_1_2_8_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr9002193"},{"key":"e_1_2_8_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00373"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.8b00467"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.0c03606"},{"key":"e_1_2_8_13_1","unstructured":"\u00a0"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-440X(99)00036-6"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr9900275"},{"key":"e_1_2_8_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr040653o"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar700066p"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.71"},{"key":"e_1_2_8_19_2","doi-asserted-by":"publisher","DOI":"10.1039\/9781849732987"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2016.02.017"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.1c00538"},{"key":"e_1_2_8_22_1","unstructured":"\u00a0"},{"key":"e_1_2_8_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00457"},{"key":"e_1_2_8_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2016.05.014"},{"key":"e_1_2_8_25_1","unstructured":"\u00a0"},{"key":"e_1_2_8_26_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar1001473"},{"key":"e_1_2_8_27_2","doi-asserted-by":"publisher","DOI":"10.1246\/bcsj.20130127"},{"key":"e_1_2_8_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11157-017-9447-9"},{"key":"e_1_2_8_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.6b00624"},{"key":"e_1_2_8_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2020.213606"},{"key":"e_1_2_8_31_2","doi-asserted-by":"publisher","DOI":"10.1039\/D0CS01291B"},{"key":"e_1_2_8_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c01180"},{"key":"e_1_2_8_33_1","unstructured":"\u00a0"},{"key":"e_1_2_8_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1187936"},{"key":"e_1_2_8_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2011.02.019"},{"key":"e_1_2_8_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja111607x"},{"key":"e_1_2_8_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2019.110877"},{"key":"e_1_2_8_38_2","doi-asserted-by":"publisher","DOI":"10.1039\/D0OB02204G"},{"key":"e_1_2_8_39_1","unstructured":"\u00a0"},{"key":"e_1_2_8_40_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp048515q"},{"key":"e_1_2_8_41_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi900144a"},{"key":"e_1_2_8_42_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja110287y"},{"key":"e_1_2_8_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.9b00862"},{"key":"e_1_2_8_44_1","unstructured":"\u00a0"},{"key":"e_1_2_8_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.05.013"},{"key":"e_1_2_8_46_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV120.007746"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar500469e"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.inorgchem.1c00265"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2017.02.027"},{"key":"e_1_2_8_50_1","unstructured":"\u00a0"},{"key":"e_1_2_8_51_2","doi-asserted-by":"publisher","DOI":"10.1107\/S1399004715002333"},{"key":"e_1_2_8_52_2","doi-asserted-by":"publisher","DOI":"10.1107\/S1399004715013073"},{"key":"e_1_2_8_53_1","unstructured":"\u00a0"},{"key":"e_1_2_8_54_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809913116"},{"key":"e_1_2_8_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201507486"},{"key":"e_1_2_8_55_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201507486"},{"key":"e_1_2_8_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201300149"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7MT00124J"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr5004908"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00775-007-0212-3"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi401517f"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.669713"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.235"},{"key":"e_1_2_8_63_1","unstructured":"\u00a0"},{"key":"e_1_2_8_64_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi980847w"},{"key":"e_1_2_8_65_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi981838q"},{"key":"e_1_2_8_66_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi990095l"},{"key":"e_1_2_8_67_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401146101"},{"key":"e_1_2_8_68_1","unstructured":"\u00a0"},{"key":"e_1_2_8_69_2","doi-asserted-by":"publisher","DOI":"10.1021\/ic060388k"},{"key":"e_1_2_8_70_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp2057173"},{"key":"e_1_2_8_71_2","doi-asserted-by":"publisher","DOI":"10.1021\/ic4006168"},{"key":"e_1_2_8_72_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00775-016-1374-7"},{"key":"e_1_2_8_73_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b06343"},{"key":"e_1_2_8_74_1","unstructured":"\u00a0"},{"key":"e_1_2_8_75_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201905119"},{"key":"e_1_2_8_76_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202104167"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"e_1_2_8_78_1","unstructured":"\u00a0"},{"key":"e_1_2_8_79_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.1c00898"},{"key":"e_1_2_8_80_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b06987"},{"key":"e_1_2_8_81_2","doi-asserted-by":"publisher","DOI":"10.1039\/D0SC02624G"},{"key":"e_1_2_8_82_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00214-008-0438-3"},{"key":"e_1_2_8_83_2","doi-asserted-by":"publisher","DOI":"10.1021\/ic701194b"},{"key":"e_1_2_8_84_2","doi-asserted-by":"publisher","DOI":"10.1039\/D0CP04848H"},{"key":"e_1_2_8_85_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b02011"},{"key":"e_1_2_8_86_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.5b02720"},{"key":"e_1_2_8_87_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201902934"},{"key":"e_1_2_8_88_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.200701739"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2011.12.014"},{"key":"e_1_2_8_90_1","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.001105"},{"key":"e_1_2_8_91_1","unstructured":"\u00a0"},{"key":"e_1_2_8_92_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr400388t"},{"key":"e_1_2_8_93_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201503802"},{"key":"e_1_2_8_94_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.0c03490"},{"key":"e_1_2_8_95_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.0c10761"},{"key":"e_1_2_8_96_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.01.016"},{"key":"e_1_2_8_97_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.1c04029"},{"key":"e_1_2_8_98_1","unstructured":"\u00a0"},{"key":"e_1_2_8_99_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.0c00983"},{"key":"e_1_2_8_100_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202101878"},{"key":"e_1_2_8_101_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.1c01993"},{"key":"e_1_2_8_102_1","unstructured":"Gaussian-09 Revision D.01 M.\u2005J. Frisch G.\u2005W. Trucks H.\u2005B. Schlegel G.\u2005E. Scuseria M.\u2005A. Robb J.\u2005R. Cheeseman G. Scalmani V. Barone B. Mennucci G.\u2005A. Petersson H. Nakatsuji M. Caricato X. Li H.\u2005P. Hratchian A.\u2005F. Izmaylov J. Bloino G. Zheng J.\u2005L. Sonnenberg M. Hada M. Ehara K. Toyota R. Fukuda J. Hasegawa M. Ishida T. Nakajima Y. Honda O. Kitao H. Nakai T. Vreven J.\u2005A. Montgomery Jr. J.\u2005E. Peralta F. Ogliaro M. Bearpark J.\u2005J. Heyd E. Brothers K.\u2005N. Kudin V.\u2005N. Staroverov T. Keith R. Kobayashi J. Normand K. Raghavachari A. Rendell J.\u2005C. Burant S.\u2005S. Iyengar J. Tomasi M. Cossi N. Rega J.\u2005M. Millam M. Klene J.\u2005E. Knox J.\u2005B. Cross V. Bakken C. Adamo J. Jaramillo R. Gomperts R.\u2005E. Stratmann O. Yazyev A.\u2005J. Austin R. Cammi C. Pomelli J.\u2005W. Ochterski R.\u2005L. Martin K. Morokuma V.\u2005G. Zakrzewski G.\u2005A. Voth P. Salvador J.\u2005J. Dannenberg S. Dapprich A.\u2005D. Daniels O. Farkas J.\u2005B. Foresman J.\u2005V. Ortiz J. Cioslowski D.\u2005J. Fox Gaussian Inc. Wallingford CT 2010."},{"key":"e_1_2_8_103_1","unstructured":"\u00a0"},{"key":"e_1_2_8_104_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.464913"},{"key":"e_1_2_8_105_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevB.37.785"},{"key":"e_1_2_8_106_1","unstructured":"\u00a0"},{"key":"e_1_2_8_107_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.448799"},{"key":"e_1_2_8_108_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.1674902"},{"key":"e_1_2_8_109_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr9904009"},{"key":"e_1_2_8_110_1","unstructured":"\u00a0"},{"key":"e_1_2_8_111_2","doi-asserted-by":"publisher","DOI":"10.1021\/ic502803b"},{"key":"e_1_2_8_112_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpca.6b09765"},{"key":"e_1_2_8_113_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b05027"},{"key":"e_1_2_8_114_1","unstructured":"\u00a0"},{"key":"e_1_2_8_115_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201604361"},{"key":"e_1_2_8_116_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201700363"}],"container-title":["ChemBioChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.202200257","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cbic.202200257","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.202200257","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T12:11:24Z","timestamp":1760271084000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cbic.202200257"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,23]]},"references-count":117,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2022,7,5]]}},"alternative-id":["10.1002\/cbic.202200257"],"URL":"https:\/\/doi.org\/10.1002\/cbic.202200257","archive":["Portico"],"relation":{},"ISSN":["1439-4227","1439-7633"],"issn-type":[{"value":"1439-4227","type":"print"},{"value":"1439-7633","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,23]]},"assertion":[{"value":"2022-05-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202200257"}}