{"id":"https://openalex.org/W4205451998","doi":"https://doi.org/10.1021/acs.jcim.1c01036","title":"Impact of PROTAC Linker Plasticity on the Solution Conformations and Dissociation of the Ternary Complex","display_name":"Impact of PROTAC Linker Plasticity on the Solution Conformations and Dissociation of the Ternary Complex","publication_year":2022,"publication_date":"2022-01-12","ids":{"openalex":"https://openalex.org/W4205451998","doi":"https://doi.org/10.1021/acs.jcim.1c01036","pmid":"https://pubmed.ncbi.nlm.nih.gov/35018781"},"language":"en","primary_location":{"id":"doi:10.1021/acs.jcim.1c01036","is_oa":false,"landing_page_url":"https://doi.org/10.1021/acs.jcim.1c01036","pdf_url":null,"source":{"id":"https://openalex.org/S167262187","display_name":"Journal of Chemical Information and Modeling","issn_l":"1549-9596","issn":["1549-9596","1549-960X"],"is_oa":false,"is_in_doaj":false,"is_core":true,"host_organization":"https://openalex.org/P4310320006","host_organization_name":"American Chemical Society","host_organization_lineage":["https://openalex.org/P4310320006"],"host_organization_lineage_names":["American Chemical Society"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Chemical Information and Modeling","raw_type":"journal-article"},"type":"article","indexed_in":["crossref","pubmed"],"open_access":{"is_oa":false,"oa_status":"closed","oa_url":null,"any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5002974209","display_name":"Dhanushka Weerakoon","orcid":null},"institutions":[{"id":"https://openalex.org/I4210143795","display_name":"AstraZeneca (Sweden)","ror":"https://ror.org/04wwrrg31","country_code":"SE","type":"company","lineage":["https://openalex.org/I105036370","https://openalex.org/I4210143795"]}],"countries":["SE"],"is_corresponding":false,"raw_author_name":"Dhanushka Weerakoon","raw_affiliation_strings":["Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden"],"affiliations":[{"raw_affiliation_string":"Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden","institution_ids":["https://openalex.org/I4210143795"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5025208579","display_name":"Rodrigo J. Carbajo","orcid":"https://orcid.org/0000-0002-0312-6499"},"institutions":[{"id":"https://openalex.org/I105036370","display_name":"AstraZeneca (United Kingdom)","ror":"https://ror.org/04r9x1a08","country_code":"GB","type":"company","lineage":["https://openalex.org/I105036370"]}],"countries":["GB"],"is_corresponding":false,"raw_author_name":"Rodrigo J. Carbajo","raw_affiliation_strings":["Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0QA, United Kingdom"],"affiliations":[{"raw_affiliation_string":"Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0QA, United Kingdom","institution_ids":["https://openalex.org/I105036370"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5031181295","display_name":"Leonardo De Maria","orcid":"https://orcid.org/0000-0002-8061-4242"},"institutions":[{"id":"https://openalex.org/I4210143795","display_name":"AstraZeneca (Sweden)","ror":"https://ror.org/04wwrrg31","country_code":"SE","type":"company","lineage":["https://openalex.org/I105036370","https://openalex.org/I4210143795"]}],"countries":["SE"],"is_corresponding":false,"raw_author_name":"Leonardo De Maria","raw_affiliation_strings":["Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden"],"affiliations":[{"raw_affiliation_string":"Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden","institution_ids":["https://openalex.org/I4210143795"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5051401603","display_name":"Christian Tyrchan","orcid":"https://orcid.org/0000-0002-6470-984X"},"institutions":[{"id":"https://openalex.org/I4210143795","display_name":"AstraZeneca (Sweden)","ror":"https://ror.org/04wwrrg31","country_code":"SE","type":"company","lineage":["https://openalex.org/I105036370","https://openalex.org/I4210143795"]}],"countries":["SE"],"is_corresponding":false,"raw_author_name":"Christian Tyrchan","raw_affiliation_strings":["Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden"],"affiliations":[{"raw_affiliation_string":"Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden","institution_ids":["https://openalex.org/I4210143795"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5103064397","display_name":"Hongtao Zhao","orcid":"https://orcid.org/0000-0002-9318-1052"},"institutions":[{"id":"https://openalex.org/I4210143795","display_name":"AstraZeneca (Sweden)","ror":"https://ror.org/04wwrrg31","country_code":"SE","type":"company","lineage":["https://openalex.org/I105036370","https://openalex.org/I4210143795"]}],"countries":["SE"],"is_corresponding":true,"raw_author_name":"Hongtao Zhao","raw_affiliation_strings":["Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden"],"affiliations":[{"raw_affiliation_string":"Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden","institution_ids":["https://openalex.org/I4210143795"]}]}],"institutions":[],"countries_distinct_count":2,"institutions_distinct_count":5,"corresponding_author_ids":["https://openalex.org/A5103064397"],"corresponding_institution_ids":["https://openalex.org/I4210143795"],"apc_list":null,"apc_paid":null,"fwci":6.7748,"has_fulltext":false,"cited_by_count":82,"citation_normalized_percentile":{"value":0.97986044,"is_in_top_1_percent":false,"is_in_top_10_percent":true},"cited_by_percentile_year":{"min":99,"max":100},"biblio":{"volume":"62","issue":"2","first_page":"340","last_page":"349"},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T12534","display_name":"Protein Degradation and Inhibitors","score":1.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T12534","display_name":"Protein Degradation and Inhibitors","score":1.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T12505","display_name":"Peptidase Inhibition and Analysis","score":0.9979000091552734,"subfield":{"id":"https://openalex.org/subfields/2730","display_name":"Oncology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T11041","display_name":"Ubiquitin and proteasome pathways","score":0.996999979019165,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/ternary-complex","display_name":"Ternary complex","score":0.7509558796882629},{"id":"https://openalex.org/keywords/linker","display_name":"Linker","score":0.727013111114502},{"id":"https://openalex.org/keywords/chemistry","display_name":"Chemistry","score":0.7028992176055908},{"id":"https://openalex.org/keywords/molecular-dynamics","display_name":"Molecular dynamics","score":0.6033695936203003},{"id":"https://openalex.org/keywords/intramolecular-force","display_name":"Intramolecular force","score":0.5522560477256775},{"id":"https://openalex.org/keywords/biophysics","display_name":"Biophysics","score":0.5410164594650269},{"id":"https://openalex.org/keywords/dissociation","display_name":"Dissociation (chemistry)","score":0.5017609596252441},{"id":"https://openalex.org/keywords/ternary-operation","display_name":"Ternary operation","score":0.501115083694458},{"id":"https://openalex.org/keywords/stereochemistry","display_name":"Stereochemistry","score":0.3092579245567322},{"id":"https://openalex.org/keywords/computational-chemistry","display_name":"Computational chemistry","score":0.2900261878967285},{"id":"https://openalex.org/keywords/biochemistry","display_name":"Biochemistry","score":0.1377761960029602},{"id":"https://openalex.org/keywords/organic-chemistry","display_name":"Organic chemistry","score":0.12651047110557556}],"concepts":[{"id":"https://openalex.org/C86756495","wikidata":"https://www.wikidata.org/wiki/Q7702931","display_name":"Ternary complex","level":3,"score":0.7509558796882629},{"id":"https://openalex.org/C2780557392","wikidata":"https://www.wikidata.org/wiki/Q523796","display_name":"Linker","level":2,"score":0.727013111114502},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.7028992176055908},{"id":"https://openalex.org/C59593255","wikidata":"https://www.wikidata.org/wiki/Q901663","display_name":"Molecular dynamics","level":2,"score":0.6033695936203003},{"id":"https://openalex.org/C75079739","wikidata":"https://www.wikidata.org/wiki/Q1571801","display_name":"Intramolecular force","level":2,"score":0.5522560477256775},{"id":"https://openalex.org/C12554922","wikidata":"https://www.wikidata.org/wiki/Q7100","display_name":"Biophysics","level":1,"score":0.5410164594650269},{"id":"https://openalex.org/C102931765","wikidata":"https://www.wikidata.org/wiki/Q189673","display_name":"Dissociation (chemistry)","level":2,"score":0.5017609596252441},{"id":"https://openalex.org/C64452783","wikidata":"https://www.wikidata.org/wiki/Q1524945","display_name":"Ternary operation","level":2,"score":0.501115083694458},{"id":"https://openalex.org/C71240020","wikidata":"https://www.wikidata.org/wiki/Q186011","display_name":"Stereochemistry","level":1,"score":0.3092579245567322},{"id":"https://openalex.org/C147597530","wikidata":"https://www.wikidata.org/wiki/Q369472","display_name":"Computational chemistry","level":1,"score":0.2900261878967285},{"id":"https://openalex.org/C55493867","wikidata":"https://www.wikidata.org/wiki/Q7094","display_name":"Biochemistry","level":1,"score":0.1377761960029602},{"id":"https://openalex.org/C178790620","wikidata":"https://www.wikidata.org/wiki/Q11351","display_name":"Organic chemistry","level":1,"score":0.12651047110557556},{"id":"https://openalex.org/C111919701","wikidata":"https://www.wikidata.org/wiki/Q9135","display_name":"Operating system","level":1,"score":0.0},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.0},{"id":"https://openalex.org/C41008148","wikidata":"https://www.wikidata.org/wiki/Q21198","display_name":"Computer science","level":0,"score":0.0},{"id":"https://openalex.org/C199360897","wikidata":"https://www.wikidata.org/wiki/Q9143","display_name":"Programming language","level":1,"score":0.0},{"id":"https://openalex.org/C181199279","wikidata":"https://www.wikidata.org/wiki/Q8047","display_name":"Enzyme","level":2,"score":0.0}],"mesh":[{"descriptor_ui":"D009687","descriptor_name":"Nuclear Proteins","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D009687","descriptor_name":"Nuclear Proteins","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D009687","descriptor_name":"Nuclear Proteins","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D014157","descriptor_name":"Transcription Factors","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":false},{"descriptor_ui":"D014157","descriptor_name":"Transcription Factors","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":false},{"descriptor_ui":"D014157","descriptor_name":"Transcription Factors","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":false},{"descriptor_ui":"D044767","descriptor_name":"Ubiquitin-Protein Ligases","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D044767","descriptor_name":"Ubiquitin-Protein Ligases","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D044767","descriptor_name":"Ubiquitin-Protein Ligases","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D044767","descriptor_name":"Ubiquitin-Protein Ligases","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D044767","descriptor_name":"Ubiquitin-Protein Ligases","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D044767","descriptor_name":"Ubiquitin-Protein Ligases","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D059748","descriptor_name":"Proteolysis","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D059748","descriptor_name":"Proteolysis","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D059748","descriptor_name":"Proteolysis","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false}],"locations_count":2,"locations":[{"id":"doi:10.1021/acs.jcim.1c01036","is_oa":false,"landing_page_url":"https://doi.org/10.1021/acs.jcim.1c01036","pdf_url":null,"source":{"id":"https://openalex.org/S167262187","display_name":"Journal of Chemical Information and Modeling","issn_l":"1549-9596","issn":["1549-9596","1549-960X"],"is_oa":false,"is_in_doaj":false,"is_core":true,"host_organization":"https://openalex.org/P4310320006","host_organization_name":"American Chemical Society","host_organization_lineage":["https://openalex.org/P4310320006"],"host_organization_lineage_names":["American Chemical Society"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Chemical Information and Modeling","raw_type":"journal-article"},{"id":"pmid:35018781","is_oa":false,"landing_page_url":"https://pubmed.ncbi.nlm.nih.gov/35018781","pdf_url":null,"source":{"id":"https://openalex.org/S4306525036","display_name":"PubMed","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of chemical information and modeling","raw_type":null}],"best_oa_location":null,"sustainable_development_goals":[{"display_name":"Clean water and sanitation","score":0.5699999928474426,"id":"https://metadata.un.org/sdg/6"}],"awards":[],"funders":[],"has_content":{"pdf":false,"grobid_xml":false},"content_urls":null,"referenced_works_count":50,"referenced_works":["https://openalex.org/W1572609533","https://openalex.org/W1966231180","https://openalex.org/W1980776518","https://openalex.org/W1988076192","https://openalex.org/W1988566244","https://openalex.org/W2003240840","https://openalex.org/W2032314598","https://openalex.org/W2035199159","https://openalex.org/W2045683699","https://openalex.org/W2054103452","https://openalex.org/W2057477511","https://openalex.org/W2068455168","https://openalex.org/W2102375526","https://openalex.org/W2116479507","https://openalex.org/W2118233996","https://openalex.org/W2129153475","https://openalex.org/W2135328202","https://openalex.org/W2141273392","https://openalex.org/W2147993766","https://openalex.org/W2149801992","https://openalex.org/W2161605421","https://openalex.org/W2165779834","https://openalex.org/W2169789938","https://openalex.org/W2171268876","https://openalex.org/W2227431445","https://openalex.org/W2234248612","https://openalex.org/W2237051895","https://openalex.org/W2283442479","https://openalex.org/W2310322011","https://openalex.org/W2312634253","https://openalex.org/W2470671857","https://openalex.org/W2530302741","https://openalex.org/W2553908226","https://openalex.org/W2597078857","https://openalex.org/W2767251210","https://openalex.org/W2806672448","https://openalex.org/W2908916952","https://openalex.org/W2909353434","https://openalex.org/W2913446986","https://openalex.org/W2914587883","https://openalex.org/W2938148420","https://openalex.org/W2948220248","https://openalex.org/W3045203019","https://openalex.org/W3045454055","https://openalex.org/W3047741243","https://openalex.org/W3088011183","https://openalex.org/W3088870471","https://openalex.org/W3117557114","https://openalex.org/W3118317455","https://openalex.org/W3130894852"],"related_works":["https://openalex.org/W2066271730","https://openalex.org/W2903092952","https://openalex.org/W2375120246","https://openalex.org/W1970737693","https://openalex.org/W1553817525","https://openalex.org/W2322757183","https://openalex.org/W2072179000","https://openalex.org/W2005358849","https://openalex.org/W2365603750","https://openalex.org/W3192101209"],"abstract_inverted_index":{"The":[0,68,149],"conformational":[1,66],"behavior":[2],"of":[3,17,25,57,70,90,98,104,110,152,173,184],"a":[4,45,105,127,138],"small":[5],"molecule":[6],"free":[7,15],"in":[8,72,101,117,136],"solution":[9],"is":[10,115,123],"important":[11],"to":[12,19,33,43,125,161,190],"understand":[13,95],"the":[14,41,52,79,88,96,102,108,111,146,153,171,185],"energy":[16],"binding":[18,160],"its":[20],"target.":[21],"This":[22],"could":[23],"be":[24,191],"special":[26],"interest":[27],"for":[28,87],"proteolysis-targeting":[29],"chimeras":[30],"(PROTACs)":[31],"due":[32],"their":[34,162],"often":[35],"flexible":[36],"and":[37,40,61,122,133,165],"lengthy":[38],"linkers":[39],"need":[42],"induce":[44],"ternary":[46,106],"complex.":[47],"Here,":[48],"we":[49],"report":[50],"on":[51,170],"molecular":[53],"dynamics":[54],"(MD)":[55],"simulations":[56,121],"two":[58,147,154,186],"PROTACs,":[59],"MZ1":[60,71,132],"dBET6,":[62],"revealing":[63],"different":[64],"linker":[65,99],"behaviors.":[67],"simulation":[69],"dimethyl":[73],"sulfoxide":[74],"(DMSO)":[75],"agrees":[76],"well":[77],"with":[78],"nuclear":[80],"magnetic":[81],"resonance":[82],"study,":[83],"providing":[84],"strong":[85],"support":[86],"relevance":[89],"our":[91],"simulations.":[92],"To":[93],"further":[94],"role":[97],"plasticity":[100],"formation":[103],"complex,":[107],"dissociation":[109],"complex":[112],"von":[113],"Hippel-Lindau-MZ1-BRD4":[114],"investigated":[116],"detail":[118],"by":[119],"steered":[120],"shown":[124],"follow":[126],"two-step":[128],"pathway.":[129],"Interestingly,":[130],"both":[131],"dBET6":[134],"display":[135],"water,":[137],"tendency":[139],"toward":[140],"an":[141,168],"intramolecular":[142],"lipophilic":[143],"interaction":[144],"between":[145],"warheads.":[148],"hydrophobic":[150,182],"contact":[151,183],"warheads":[155,187],"would":[156],"prevent":[157],"them":[158],"from":[159],"respective":[163],"proteins":[164],"might":[166],"have":[167],"effect":[169],"efficacy":[172],"induced":[174],"cellular":[175],"protein":[176],"degradation.":[177],"However,":[178],"conformations":[179],"featuring":[180],"this":[181],"are":[188],"calculated":[189],"marginally":[192],"more":[193],"favorable.":[194]},"counts_by_year":[{"year":2026,"cited_by_count":4},{"year":2025,"cited_by_count":25},{"year":2024,"cited_by_count":26},{"year":2023,"cited_by_count":13},{"year":2022,"cited_by_count":14}],"updated_date":"2026-04-03T22:45:19.894376","created_date":"2025-10-10T00:00:00"}