{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T11:27:47Z","timestamp":1782818867857,"version":"3.54.5"},"reference-count":42,"publisher":"Wiley","issue":"26","license":[{"start":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:00:00Z","timestamp":1661385600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Comput Chem"],"published-print":{"date-parts":[[2022,10,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Drug resistant\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    , which mostly results from single nucleotide polymorphisms in antibiotic target genes, poses a major threat to tuberculosis treatment outcomes. Relative binding free energy (RBFE) calculations can rapidly predict the effects of mutations, but this approach has not been tested on large, complex proteins. We use RBFE calculations to predict the effects of\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    RNA polymerase and DNA gyrase mutations on rifampicin and moxifloxacin susceptibility respectively. These mutations encompass a range of amino acid substitutions with known effects and include large steric perturbations and charged moieties. We find that moderate numbers (\n                    <jats:italic>n\u2009=<\/jats:italic>\n                    \u00a03\u201315) of short RBFE calculations can predict resistance in cases where the mutation results in a large change in the binding free energy. We show that the method lacks discrimination in cases with either a small change in energy or that involve charged amino acids, and we investigate how these calculation errors may be decreased.\n                  <\/jats:p>","DOI":"10.1002\/jcc.26979","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T12:04:28Z","timestamp":1661429068000},"page":"1771-1782","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Predicting antibiotic resistance in complex protein targets using alchemical free energy methods"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5070-6525","authenticated-orcid":false,"given":"Alice E.","family":"Brankin","sequence":"first","affiliation":[{"name":"Nuffield Department of Medicine, John Radcliffe Hospital University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0912-4483","authenticated-orcid":false,"given":"Philip W.","family":"Fowler","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine, John Radcliffe Hospital University of Oxford  Oxford UK"},{"name":"National Institute of Health Research Oxford Biomedical Research Centre John Radcliffe Hospital  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"World Health Organization (WHO) Rapid communication: Key changes to treatment of multidrug\u2010 and rifampicin\u2010resistant tuberculosis (MDR\/RR\u2010TB)2018."},{"key":"e_1_2_9_3_1","unstructured":"World Health Organization (WHO) Catalogue of mutations inMycobacterium tuberculosiscomplex and their association with drug resistance. License: CC BY\u2010NC\u2010SA 3.0 IGO.2021."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(21)00301-3"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001721"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1800474"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0907847"},{"key":"e_1_2_9_8_1","unstructured":"World Health Organization (WHO).WHO policy statement: Automated real\u2010time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB\/RIF system2011 Accessed July 24 2014.http:\/\/whqlibdoc.who.int\/publications\/2011\/9789241501545_eng.pdf."},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1413930"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.02775-15"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01354-2017"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00062-6"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/2021.09.14.460353"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.4.773"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02169-16"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.06272-11"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja512751q"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9SC03754C"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.5b00538"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-3233(03)66002-X"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp505332p"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2017.12.009"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-018-0075-x"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.9b00590"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.8b01118"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsfs.2019.0141"},{"key":"e_1_2_9_27_1","unstructured":"World Health Organization (WHO) Technical report on critical concentrations for drug susceptibility testing of isoniazid and the rifamycins (rifampicin rifabutin and rifapentine) 2021."},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1525047113"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.03.001"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btg362"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.22711"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.softx.2015.06.001"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.23804"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct501111d"},{"issue":"1","key":"e_1_2_9_36_1","first-page":"18378","volume":"2","author":"Mey A. 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