{"doi":"10.1073/pnas.1831920100","title":"How protein thermodynamics and folding mechanisms are altered by the chaperonin cage: Molecular simulations","abstract":"<jats:p>\n            How the\n            <jats:italic>Escherichia coli</jats:italic>\n            GroEL/ES chaperonin assists folding of a substrate protein remains to be uncovered. Recently, it was suggested that confinement into the chaperonin cage itself can significantly accelerate folding of a substrate. Performing comprehensive molecular simulations of eight proteins confined into various sizes\n            <jats:italic>L</jats:italic>\n            of chaperonin-like cage, we explore how and to what extent protein thermodynamics and folding mechanisms are altered by the cage. We show that a substrate protein is remarkably stabilized by confinement; the estimated increase in denaturation temperature Δ\n            <jats:italic>T</jats:italic>\n            <jats:sub>f</jats:sub>\n            is as large as ≈60°C. For a protein of size\n            <jats:italic>R</jats:italic>\n            <jats:sub>0</jats:sub>\n            , the stabilization Δ\n            <jats:italic>T</jats:italic>\n            <jats:sub>f</jats:sub>\n            scales as (\n            <jats:italic>R</jats:italic>\n            <jats:sub>0</jats:sub>\n            /\n            <jats:italic>L</jats:italic>\n            )\n            <jats:sup>ν</jats:sup>\n            , where ν ≈ 3, which is consistent with a mean field theory of polymer. We also found significant free energy cost of confining a protein, which increases with\n            <jats:italic>R</jats:italic>\n            <jats:sub>0</jats:sub>\n            /\n            <jats:italic>L</jats:italic>\n            , indicating that the confinement requires external work provided by the chaperonin system. In kinetic study, we show the folding is accelerated in a modestly well confined case, which is consistent with a recent experimental result on ribulose-1,5-bisphosphate carboxylase-oxygenase folding and simulation results of a β hairpin. Interestingly, the acceleration of folding is likely to be larger for a protein with more complex topology, as quantified by the contact order. We also show how ensemble of folding pathways are altered by the chaperonin-like cage calculating a variant of φ value used in the study of spontaneous folding.\n          </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2003,"id":24533,"datarank":11.393185842638745,"base_score":5.420534999272286,"endowment":5.420534999272286,"self_citation_contribution":0.813080249890843,"citation_network_contribution":10.580105592747902,"self_endowment_contribution":0.813080249890843,"citer_contribution":10.580105592747902,"corpus_percentile":null,"corpus_rank":null,"citation_count":225,"citer_count":200,"citers_with_citation_signal":192,"citers_with_endowment":192,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":146930,"name":"Nobuyasu Koga","orcid":null,"position":1,"is_corresponding":false},{"id":121714,"name":"Shoji Takada","orcid":null,"position":2,"is_corresponding":false},{"id":146929,"name":"Fumiko Takagi","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":5.420534999272286,"endowment":5.420534999272286,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"12947041","pmcid":"PMC208763","openalex_id":"https://openalex.org/W2059164257","authors":[],"funders":[],"total_grants":0,"fwci":5.4977,"citation_percentile":0.96765968,"influential_citations":7,"citation_trend":[{"year":2012,"count":12},{"year":2013,"count":15},{"year":2014,"count":13},{"year":2015,"count":10},{"year":2016,"count":3},{"year":2017,"count":8},{"year":2018,"count":8},{"year":2019,"count":4},{"year":2020,"count":6},{"year":2021,"count":8},{"year":2022,"count":3},{"year":2024,"count":3},{"year":2025,"count":5},{"year":2026,"count":4}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/208763","host_type":"repository"},{"url":"https://europepmc.org/articles/pmc208763?pdf=render","host_type":"GREEN"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/208763","host_type":"repository"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.1831920100","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.1831920100","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/12947041","host_type":"repository"},{"url":"http://europepmc.org/pmc/articles/PMC208763","host_type":"repository"}],"fields_of_study":["Protein Structure and Dynamics","Heat shock proteins research","Enzyme Structure and Function","Chemistry","Medicine","Physics","Chaperonins","Kinetics","Protein Folding","Proteins","Thermodynamics"],"mesh_terms":["Kinetics","Proteins","Thermodynamics","Protein Folding","Chaperonins"],"keywords":["Chaperonin","GroEL","Protein folding","Folding (DSP implementation)","Contact order","Downhill folding","GroES","Biophysics","Phi value analysis","Chemistry","Topology (electrical circuits)","Crystallography","Thermodynamics","Chemical physics","Physics","Biology","Biochemistry","Escherichia coli"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Affordable and clean energy"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-07T22:37:40.168389Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}