{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T02:41:32Z","timestamp":1767926492625,"version":"3.49.0"},"reference-count":82,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2016,6,22]],"date-time":"2016-06-22T00:00:00Z","timestamp":1466553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["EXPL\/BBB-BQB\/0749\/2013"],"award-info":[{"award-number":["EXPL\/BBB-BQB\/0749\/2013"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["EXPL\/BBB-BQB\/0749\/2013"],"award-info":[{"award-number":["EXPL\/BBB-BQB\/0749\/2013"]}]}],"content-domain":{"domain":["rsc.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,6,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We employed high-temperature classical molecular dynamics (MD) simulations to investigate the unfolding process of the wild-type (WT) and F508del-NBD1 domains of CFTR protein, with and without second-site mutations. To rationalize the in vitro behavior of F508del-NBD1, namely its lower folding yield and higher aggregation propensity, we focused our analysis of the MD data on the existence of intermediate states with aggregation potential and\/or stabilized by a significant number of non-native interactions (i.e. misfolded states). We find that the deletion of phenylalanine 508 is able to forcefully reshape the conformational space of the NBD1 domain to the extent that it uniquely populates intermediate states whose structural traits provide important insights into the molecular events that underlie the impaired folding of F508del-NBD1. In particular, our simulations predict the formation of a misfolded intermediate whose population is highly enhanced by deletion of residue 508. The stabilization of this intermediate is a direct consequence of the enhanced non-native coupling between various key regions of the \u03b1-helical subdomain and ATP-binding subdomain; it is singularly characterized by a set of non-native interactions within the ATP-binding subdomain and between that domain and the \u03b1-helical subdomain region. The formation of this intermediate is not blocked by second-site suppressor mutations which indicates a limited role of the latter in correcting the rather complex folding process of the CFTR protein missing residue 508.<\/jats:p>\n                  <jats:p\/>","DOI":"10.1039\/c6mb00193a","type":"journal-article","created":{"date-parts":[[2016,6,22]],"date-time":"2016-06-22T16:23:21Z","timestamp":1466612601000},"page":"2834-2848","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Thermal unfolding simulations of NBD1 domain variants reveal structural motifs associated with the impaired folding of F508del-CFTR"],"prefix":"10.1093","volume":"12","author":[{"given":"S\u00edlvia G","family":"Est\u00e1cio","sequence":"first","affiliation":[{"name":"BioISI \u2013 Biosystems & Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa a , Campo Grande, C8, 1749-016 Lisboa Portugal \u00a0 silviagestacio@gmail.com \u00a0 pffaisca@fc.ul.pt"}]},{"given":"Hugo F. M C","family":"Martiniano","sequence":"additional","affiliation":[{"name":"BioISI \u2013 Biosystems & Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa a , Campo Grande, C8, 1749-016 Lisboa Portugal \u00a0 silviagestacio@gmail.com \u00a0 pffaisca@fc.ul.pt"}]},{"given":"Patr\u00edcia F N","family":"Fa\u00edsca","sequence":"additional","affiliation":[{"name":"Departamento de F\u00edsica, Faculdade de Ci\u00eancias, Universidade de Lisboa b , Campo Grande, C8, 1749-016 Lisboa Portugal"},{"name":"BioISI \u2013 Biosystems & Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa a , Campo Grande, C8, 1749-016 Lisboa Portugal \u00a0 silviagestacio@gmail.com \u00a0 pffaisca@fc.ul.pt"}]}],"member":"286","published-online":{"date-parts":[[2016,6,22]]},"reference":[{"key":"2026010815204682000_cit1","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1126\/science.2475911","article-title":"et al., Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA","volume":"245","author":"Riordan","year":"1989","journal-title":"Science"},{"key":"2026010815204682000_cit2","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.jmb.2009.11.051","article-title":"et al., Structure and Dynamics of NBD1 from CFTR Characterized Using Crystallography and Hydrogen\/Deuterium Exchange Mass Spectrometry","volume":"396","author":"Lewis","year":"2010","journal-title":"J. Mol. Biol."},{"key":"2026010815204682000_cit3","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1038\/nature03313","article-title":"CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains","volume":"433","author":"Vergani","year":"2005","journal-title":"Nature"},{"key":"2026010815204682000_cit4","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature04712","article-title":"The ABC protein turned chloride channel whose failure causes cystic fibrosis","volume":"440","author":"Gadsby","year":"2006","journal-title":"Nature"},{"key":"2026010815204682000_cit5","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1113\/jphysiol.2009.171595","article-title":"Gating of the CFTR Cl\u2212 channel by ATP-driven nucleotide-binding domain dimerisation","volume":"587","author":"Hwang","year":"2009","journal-title":"J. Physiol."},{"key":"2026010815204682000_cit6","doi-asserted-by":"crossref","first-page":"4728","DOI":"10.1038\/sj.emboj.7601373","article-title":"et al.In vivo phosphorylation of CFTR promotes formation of a nucleotide-binding domain heterodimer","volume":"25","author":"Mense","year":"2006","journal-title":"EMBO J."},{"key":"2026010815204682000_cit7","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1038\/nsmb1278","article-title":"et al., CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices","volume":"14","author":"Baker","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026010815204682000_cit8","doi-asserted-by":"crossref","first-page":"3469","DOI":"10.1007\/s00018-009-0133-0","article-title":"Molecular models of the open and closed states of the whole human CFTR protein","volume":"66","author":"Mornon","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"2026010815204682000_cit9","doi-asserted-by":"crossref","first-page":"3256","DOI":"10.1073\/pnas.0800254105","article-title":"et al., Phenylalanine-508 mediates a cytoplasmic\u2013membrane domain contact in the CFTR 3D structure crucial to assembly and channel function","volume":"105","author":"Serohijos","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026010815204682000_cit10","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/0092-8674(90)90148-8","article-title":"et al., Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis","volume":"63","author":"Cheng","year":"1990","journal-title":"Cell"},{"key":"2026010815204682000_cit11","doi-asserted-by":"crossref","first-page":"7261","DOI":"10.1074\/jbc.271.13.7261","article-title":"Alteration of the Cystic Fibrosis Transmembrane Conductance Regulator Folding Pathway: Effects of the \u0394F508 Mutation on the Thermodynamic Stability and Folding Yield of NBD1","volume":"271","author":"Qu","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2026010815204682000_cit12","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.chembiol.2007.11.012","article-title":"et al., Solubilizing Mutations Used to Crystallize One CFTR Domain Attenuate the Trafficking and Channel Defects Caused by the Major Cystic Fibrosis Mutation","volume":"15","author":"Pissarra","year":"2008","journal-title":"Chem. Biol."},{"key":"2026010815204682000_cit13","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/354526a0","article-title":"et al., Altered chloride ion channel kinetics associated with the [Delta]F508 cystic fibrosis mutation","volume":"354","author":"Dalemans","year":"1991","journal-title":"Nature"},{"key":"2026010815204682000_cit14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/nsmb882","article-title":"The [Delta]F508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR","volume":"12","author":"Du","year":"2005","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026010815204682000_cit15","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1113\/jphysiol.2010.202861","article-title":"The most common cystic fibrosis-associated mutation destabilizes the dimeric state of the nucleotide-binding domains of CFTR","volume":"589","author":"Jih","year":"2011","journal-title":"J. Physiol."},{"key":"2026010815204682000_cit16","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.cell.2011.11.023","article-title":"et al., Requirements for Efficient Correction of \u0394F508 CFTR Revealed by Analyses of Evolved Sequences","volume":"148","author":"Mendoza","year":"2012","journal-title":"Cell"},{"key":"2026010815204682000_cit17","doi-asserted-by":"crossref","first-page":"19967","DOI":"10.1074\/jbc.M109.092684","article-title":"Potentiation of Disease-associated Cystic Fibrosis Transmembrane Conductance Regulator Mutants by Hydrolyzable ATP Analogs","volume":"285","author":"Miki","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026010815204682000_cit18","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.cell.2011.11.024","article-title":"et al., Correction of Both NBD1 Energetics and Domain Interface Is Required to Restore \u0394F508 CFTR Folding and Function","volume":"148","author":"Rabeh","year":"2012","journal-title":"Cell"},{"key":"2026010815204682000_cit19","doi-asserted-by":"crossref","first-page":"21592","DOI":"10.1016\/S0021-9258(20)80582-1","article-title":"et al., The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. Determination of functional half-lives on transfected cells","volume":"268","author":"Lukacs","year":"1993","journal-title":"J. Biol. Chem."},{"key":"2026010815204682000_cit20","doi-asserted-by":"crossref","first-page":"e1000008","DOI":"10.1371\/journal.pcbi.1000008","article-title":"Diminished Self-Chaperoning Activity of the \u0394F508 Mutant of CFTR Results in Protein Misfolding","volume":"4","author":"Serohijos","year":"2008","journal-title":"PLoS Comput. Biol."},{"key":"2026010815204682000_cit21","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/nsmb881","article-title":"Side chain and backbone contributions of Phe508 to CFTR folding","volume":"12","author":"Thibodeau","year":"2005","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026010815204682000_cit22","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1002\/pro.480","article-title":"et al., Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis","volume":"19","author":"Wang","year":"2010","journal-title":"Protein Sci."},{"key":"2026010815204682000_cit23","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1002\/pro.479","article-title":"et al., Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1","volume":"19","author":"Protasevich","year":"2010","journal-title":"Protein Sci."},{"key":"2026010815204682000_cit24","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jmb.2014.07.026","article-title":"et al., Restoration of NBD1 Thermal Stability Is Necessary and Sufficient to Correct \u0394F508 CFTR Folding and Assembly","volume":"427","author":"He","year":"2015","journal-title":"J. Mol. Biol."},{"key":"2026010815204682000_cit25","doi-asserted-by":"crossref","first-page":"35825","DOI":"10.1074\/jbc.M110.131623","article-title":"et al., The Cystic Fibrosis-causing Mutation \u0394F508 Affects Multiple Steps in Cystic Fibrosis Transmembrane Conductance Regulator Biogenesis","volume":"285","author":"Thibodeau","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026010815204682000_cit26","doi-asserted-by":"crossref","first-page":"3497","DOI":"10.2174\/13816128113199990318","article-title":"Rescuing Mutant CFTR: A Multi-task Approach to a Better Outcome in Treating Cystic Fibrosis","volume":"19","author":"Amaral","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"2026010815204682000_cit27","doi-asserted-by":"crossref","first-page":"18843","DOI":"10.1073\/pnas.1105787108","article-title":"et al., Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809","volume":"108","author":"Van Goor","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026010815204682000_cit28","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.molmed.2011.10.003","article-title":"CFTR: folding, misfolding and correcting the \u0394F508 conformational defect","volume":"18","author":"Lukacs","year":"2012","journal-title":"Trends Mol. Med."},{"key":"2026010815204682000_cit29","doi-asserted-by":"crossref","first-page":"35896","DOI":"10.1074\/jbc.M205644200","article-title":"Mutations in the Nucleotide Binding Domain 1 Signature Motif Region Rescue Processing and Functional Defects of Cystic Fibrosis Transmembrane Conductance Regulator \u0394F508","volume":"277","author":"deCarvalho","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2026010815204682000_cit30","doi-asserted-by":"crossref","first-page":"2594","DOI":"10.1007\/s00018-008-8249-1","article-title":"Atomic model of human cystic fibrosis transmembrane conductance regulator: Membrane-spanning domains and coupling interfaces","volume":"65","author":"Mornon","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"2026010815204682000_cit31","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1021\/acs.jcim.5b00312","article-title":"REMD Simulations Reveal the Dynamic Profile and Mechanism of Action of Deleterious, Rescuing, and Stabilizing Perturbations to NBD1 from CFTR","volume":"55","author":"Zhenin","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"2026010815204682000_cit32","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1007\/s00018-014-1749-2","article-title":"Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics","volume":"72","author":"Mornon","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"2026010815204682000_cit33","doi-asserted-by":"crossref","first-page":"5915","DOI":"10.1073\/pnas.1218321110","article-title":"Atomic-level description of ubiquitin folding","volume":"110","author":"Piana","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026010815204682000_cit34","doi-asserted-by":"crossref","first-page":"3031","DOI":"10.1021\/ja512605w","article-title":"Mechanism of Substrate Translocation by a Ring-Shaped ATPase Motor at Millisecond Resolution","volume":"137","author":"Ma","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"2026010815204682000_cit35","doi-asserted-by":"crossref","first-page":"5142","DOI":"10.1073\/pnas.89.11.5142","article-title":"A model of the molten globule state from molecular dynamics simulations","volume":"89","author":"Daggett","year":"1992","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026010815204682000_cit36","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1006\/jmbi.1993.1414","article-title":"Protein Unfolding Pathways Explored Through Molecular Dynamics Simulations","volume":"232","author":"Daggett","year":"1993","journal-title":"J. Mol. Biol."},{"key":"2026010815204682000_cit37","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0092-8674(02)00620-7","article-title":"Protein Folding and Unfolding at Atomic Resolution","volume":"108","author":"Fersht","year":"2002","journal-title":"Cell"},{"key":"2026010815204682000_cit38","doi-asserted-by":"crossref","first-page":"7079","DOI":"10.1021\/bi800118b","article-title":"Microscopic reversibility of protein folding in molecular dynamics simulations of the engrailed homeodomain","volume":"47","author":"McCully","year":"2008","journal-title":"Biochemistry"},{"key":"2026010815204682000_cit39","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.abb.2012.12.015","article-title":"Using simulations to provide the framework for experimental protein folding studies","volume":"531","author":"Rizzuti","year":"2013","journal-title":"Arch. Biochem. Biophys."},{"key":"2026010815204682000_cit40","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1126\/science.278.5345.1928","article-title":"\u2018New view\u2019 of protein folding reconciled with the old through multiple unfolding simulations","volume":"278","author":"Lazaridis","year":"1997","journal-title":"Science"},{"key":"2026010815204682000_cit41","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nrm1126","article-title":"The present view of the mechanism of protein folding","volume":"4","author":"Daggett","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2026010815204682000_cit42","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0022-2836(02)00672-1","article-title":"Increasing Temperature Accelerates Protein Unfolding Without Changing the Pathway of Unfolding","volume":"322","author":"Day","year":"2002","journal-title":"J. Mol. Biol."},{"key":"2026010815204682000_cit43","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1074\/jbc.M410968200","article-title":"et al., Impact of the \u0394F508 Mutation in First Nucleotide-binding Domain of Human Cystic Fibrosis Transmembrane Conductance Regulator on Domain Folding and Structure","volume":"280","author":"Lewis","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2026010815204682000_cit44","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.biochi.2009.09.007","article-title":"Molecular dynamics analysis of the wild type and dF508 mutant structures of the human CFTR\u2013nucleotide binding domain 1","volume":"92","author":"Bisignano","year":"2010","journal-title":"Biochimie"},{"key":"2026010815204682000_cit45","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.jcf.2007.11.008","article-title":"\u0394F508 mutation increases conformational flexibility of CFTR protein","volume":"7","author":"Wieczorek","year":"2008","journal-title":"J. Cystic Fibrosis"},{"key":"2026010815204682000_cit46","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0092-8674(93)90233-G","article-title":"et al., Identification of revertants for the cystic fibrosis \u0394F508 mutation using STE6-CFTR chimeras in yeast","volume":"73","author":"Teem","year":"1993","journal-title":"Cell"},{"key":"2026010815204682000_cit47","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1006\/jmbi.2001.4865","article-title":"Extending the accuracy limits of prediction for side-chain conformations","volume":"311","author":"Xiang","year":"2001","journal-title":"J. Mol. Biol."},{"key":"2026010815204682000_cit48","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1093\/bioinformatics\/btm262","article-title":"An evaluation of automated homology modelling methods at low target\u2013template sequence similarity","volume":"23","author":"Dalton","year":"2007","journal-title":"Bioinformatics"},{"key":"2026010815204682000_cit49","volume-title":"et al.","author":"Case","year":"2011"},{"key":"2026010815204682000_cit50","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"et al., GROMACS: Fast, flexible, and free","volume":"26","author":"Van Der Spoel","year":"2005","journal-title":"J. Comput. Chem."},{"key":"2026010815204682000_cit51","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1093\/bioinformatics\/btt055","article-title":"et al., GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit","volume":"29","author":"Pronk","year":"2013","journal-title":"Bioinformatics"},{"key":"2026010815204682000_cit52","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graphics"},{"key":"2026010815204682000_cit53","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"2026010815204682000_cit54","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1002\/prot.21123","article-title":"et al., Comparison of multiple Amber force fields and development of improved protein backbone parameters","volume":"65","author":"Hornak","year":"2006","journal-title":"Proteins"},{"key":"2026010815204682000_cit55","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/j.bpj.2009.04.063","article-title":"Evaluating the performance of the ff99SB force field based on NMR scalar coupling data","volume":"97","author":"Wickstrom","year":"2009","journal-title":"Biophys. J."},{"key":"2026010815204682000_cit56","doi-asserted-by":"crossref","first-page":"9020","DOI":"10.1021\/jp8001614","article-title":"Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations","volume":"112","author":"Joung","year":"2008","journal-title":"J. Phys. Chem. B"},{"key":"2026010815204682000_cit57","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/0166-1280(92)87163-T","article-title":"Modelling of ion-ligand interactions in solutions and biomolecules","volume":"256","author":"\u00c5qvist","year":"1992","journal-title":"THEOCHEM"},{"key":"2026010815204682000_cit58","doi-asserted-by":"crossref","first-page":"4163","DOI":"10.1093\/nar\/gkq150","article-title":"Differential stability of DNA crossovers in solution mediated by divalent cations","volume":"38","author":"V\u00e1rnai","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2026010815204682000_cit59","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1002\/jcc.10262","article-title":"Development of polyphosphate parameters for use with the AMBER force field","volume":"24","author":"Meagher","year":"2003","journal-title":"J. Comput. Chem."},{"key":"2026010815204682000_cit60","doi-asserted-by":"crossref","first-page":"e6516","DOI":"10.1371\/journal.pone.0006516","article-title":"Molecular Dynamics Simulation of Phosphorylated KID Post-Translational Modification","volume":"4","author":"Chen","year":"2009","journal-title":"PLoS One"},{"key":"2026010815204682000_cit61","doi-asserted-by":"crossref","first-page":"e1000689","DOI":"10.1371\/journal.pcbi.1000689","article-title":"Unfolding Simulations Reveal the Mechanism of Extreme Unfolding Cooperativity in the Kinetically Stable \u03b1-Lytic Protease","volume":"6","author":"Salimi","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"2026010815204682000_cit62","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.1529\/biophysj.106.100149","article-title":"A One-Dimensional Reaction Coordinate for Identification of Transition States from Explicit Solvent Pfold-Like Calculations","volume":"93","author":"Beck","year":"2007","journal-title":"Biophys. J."},{"key":"2026010815204682000_cit63","doi-asserted-by":"crossref","first-page":"9062","DOI":"10.1073\/pnas.96.16.9062","article-title":"Molecular dynamics simulations of unfolding and refolding of a \u03b2-hairpin fragment of protein G","volume":"96","author":"Pande","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026010815204682000_cit64","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jmgm.2003.12.005","article-title":"MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology","volume":"22","author":"Feig","year":"2004","journal-title":"J. Mol. Graphics Modell."},{"key":"2026010815204682000_cit65","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1096\/fj.09-141788","article-title":"et al., Restoration of domain folding and interdomain assembly by second-site suppressors of the \u0394F508 mutation in CFTR","volume":"24","author":"He","year":"2010","journal-title":"FASEB J."},{"key":"2026010815204682000_cit66","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3389\/fphar.2012.00160","article-title":"et al., Functional Rescue of F508del-CFTR Using Small Molecule Correctors","volume":"3","author":"Molinski","year":"2012","journal-title":"Front. Pharmacol."},{"key":"2026010815204682000_cit67","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1039\/C4SC01320D","article-title":"et al., Rational coupled dynamics network manipulation rescues disease-relevant mutant cystic fibrosis transmembrane conductance regulator","volume":"6","author":"Proctor","year":"2015","journal-title":"Chem. Sci."},{"key":"2026010815204682000_cit68","doi-asserted-by":"crossref","first-page":"009522","DOI":"10.1101\/cshperspect.a009522","article-title":"Dynamics Intrinsic to Cystic Fibrosis Transmembrane Conductance Regulator Function and Stability","volume":"3","author":"Chong","year":"2013","journal-title":"Cold Spring Harbor Perspect. Med."},{"key":"2026010815204682000_cit69","doi-asserted-by":"crossref","first-page":"14916","DOI":"10.1021\/jp108618d","article-title":"Protein Simulations with an Optimized Water Model: Cooperative Helix Formation and Temperature-Induced Unfolded State Collapse","volume":"114","author":"Best","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"2026010815204682000_cit70","doi-asserted-by":"crossref","first-page":"5113","DOI":"10.1021\/jp508971m","article-title":"Water Dispersion Interactions Strongly Influence Simulated Structural Properties of Disordered Protein States","volume":"119","author":"Piana","year":"2015","journal-title":"J. Phys. Chem. B"},{"key":"2026010815204682000_cit71","doi-asserted-by":"crossref","first-page":"85102","DOI":"10.1063\/1.4747492","article-title":"Robustness of atomistic G\u014d models in predicting native-like folding intermediates","volume":"137","author":"Est\u00e1cio","year":"2012","journal-title":"J. Chem. Phys."},{"key":"2026010815204682000_cit72","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.jmb.2012.06.020","article-title":"Identification of a Conserved Aggregation-Prone Intermediate State in the Folding Pathways of Spc-SH3 Amyloidogenic Variants","volume":"422","author":"Krobath","year":"2012","journal-title":"J. Mol. Biol."},{"key":"2026010815204682000_cit73","doi-asserted-by":"crossref","first-page":"17256","DOI":"10.3390\/ijms140917256","article-title":"Assessing the Effect of Loop Mutations in the Folding Space of \u03b22-Microglobulin with Molecular Dynamics Simulations","volume":"14","author":"Est\u00e1cio","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"2026010815204682000_cit74","doi-asserted-by":"crossref","first-page":"e1003606","DOI":"10.1371\/journal.pcbi.1003606","article-title":"et al., A simulated intermediate state for folding and aggregation provides insights into \u0394N6 \u03b22-microglobulin amyloidogenic behavior","volume":"10","author":"Est\u00e1cio","year":"2014","journal-title":"PLoS Comput. Biol."},{"key":"2026010815204682000_cit75","first-page":"373102","article-title":"The nucleation mechanism of protein folding: a survey of computer simulation studies","volume":"21","author":"Fa\u00edsca","year":"2009","journal-title":"J. Phys.: Condens. Matter"},{"key":"2026010815204682000_cit76","doi-asserted-by":"crossref","first-page":"145106","DOI":"10.1063\/1.2777150","article-title":"Pathways to folding, nucleation events and native geometry","volume":"127","author":"Travasso","year":"2007","journal-title":"J. Chem. Phys."},{"key":"2026010815204682000_cit77","doi-asserted-by":"crossref","first-page":"17874","DOI":"10.1073\/pnas.1311599110","article-title":"Native contacts determine protein folding mechanisms in atomistic simulations","volume":"110","author":"Best","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026010815204682000_cit78","doi-asserted-by":"crossref","first-page":"6352","DOI":"10.1021\/bi100807h","article-title":"The V510D Suppressor Mutation Stabilizes \u0394F508-CFTR at the Cell Surface","volume":"49","author":"Loo","year":"2010","journal-title":"Biochemistry"},{"key":"2026010815204682000_cit79","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.jmb.2010.06.019","article-title":"et al., Regulatory Insertion Removal Restores Maturation, Stability and Function of \u0394F508 CFTR","volume":"401","author":"Aleksandrov","year":"2010","journal-title":"J. Mol. Biol."},{"key":"2026010815204682000_cit80","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jmb.2012.03.001","article-title":"et al., Allosteric Modulation Balances Thermodynamic Stability and Restores Function of \u0394F508 CFTR","volume":"419","author":"Aleksandrov","year":"2012","journal-title":"J. Mol. Biol."},{"key":"2026010815204682000_cit81","doi-asserted-by":"crossref","first-page":"25421","DOI":"10.1074\/jbc.272.41.25421","article-title":"The Molecular Chaperone Hsc70 Assists the in Vitro Folding of the N-terminal Nucleotide-binding Domain of the Cystic Fibrosis Transmembrane Conductance Regulator","volume":"272","author":"Strickland","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2026010815204682000_cit82","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.molcel.2011.02.027","article-title":"Ligand-Driven Vectorial Folding of Ribosome-Bound Human CFTR NBD1","volume":"41","author":"Khushoo","year":"2011","journal-title":"Mol. 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