{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:39:21Z","timestamp":1776919161901,"version":"3.51.2"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2010,2,26]],"date-time":"2010-02-26T00:00:00Z","timestamp":1267142400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1000689","type":"journal-article","created":{"date-parts":[[2010,3,3]],"date-time":"2010-03-03T00:10:35Z","timestamp":1267575035000},"page":"e1000689","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":23,"title":["Unfolding Simulations Reveal the Mechanism of Extreme Unfolding Cooperativity in the Kinetically Stable \u03b1-Lytic Protease"],"prefix":"10.1371","volume":"6","author":[{"given":"Neema L.","family":"Salimi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bosco","family":"Ho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Agard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2010,2,26]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/27470","article-title":"Unfolded conformations of alpha-lytic protease are more stable than its native state.","volume":"395","author":"JL Sohl","year":"1998","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/415343a","article-title":"Energetic landscape of alpha-lytic protease optimizes longevity through kinetic stability.","volume":"415","author":"SS Jaswal","year":"2002","journal-title":"Nature"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1110\/ps.03336804","article-title":"The folding landscape of Streptomyces griseus protease B reveals the energetic costs and benefits associated with evolving kinetic stability.","volume":"13","author":"SM Truhlar","year":"2004","journal-title":"Protein Sci"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1110\/ps.03389704","article-title":"Disabling the folding catalyst is the last critical step in alpha-lytic protease folding.","volume":"13","author":"EL Cunningham","year":"2004","journal-title":"Protein Sci"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.jmb.2005.01.032","article-title":"Comprehensive analysis of protein folding activation thermodynamics reveals a universal behavior violated by kinetically stable proteases.","volume":"347","author":"SS Jaswal","year":"2005","journal-title":"J Mol Biol"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.jmb.2007.02.032","article-title":"Structural and mechanistic exploration of acid resistance: kinetic stability facilitates evolution of extremophilic behavior.","volume":"368","author":"BA Kelch","year":"2007","journal-title":"J Mol Biol"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.jmb.2007.04.078","article-title":"Mesophile versus thermophile: insights into the structural mechanisms of kinetic stability.","volume":"370","author":"BA Kelch","year":"2007","journal-title":"J Mol Biol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/prot.20525","article-title":"The folding landscape of an alpha-lytic protease variant reveals the role of a conserved beta-hairpin in the development of kinetic stability.","volume":"61","author":"SM Truhlar","year":"2005","journal-title":"Proteins"},{"key":"ref9","first-page":"771","article-title":"The folding of an enzyme. I. Theory of protein engineering analysis of stability and pathway of protein folding.","volume":"224","author":"AR Fersht","year":"1992","journal-title":"J Mol Biol"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1006\/jmbi.1995.0616","article-title":"The structure of the transition state for folding of chymotrypsin inhibitor 2 analysed by protein engineering methods: evidence for a nucleation-condensation mechanism for protein folding.","volume":"254","author":"LS Itzhaki","year":"1995","journal-title":"J Mol Biol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1073\/pnas.97.4.1525","article-title":"Transition-state structure as a unifying basis in protein-folding mechanisms: contact order, chain topology, stability, and the extended nucleus mechanism.","volume":"97","author":"AR Fersht","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/340122a0","article-title":"Mapping the transition-state and pathway of protein folding by protein engineering.","volume":"340","author":"A Matouschek","year":"1989","journal-title":"Nature"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"10430","DOI":"10.1073\/pnas.91.22.10430","article-title":"Characterization of the transition state of protein unfolding by use of molecular dynamics: chymotrypsin inhibitor 2.","volume":"91","author":"A Li","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1006\/jmbi.1996.0172","article-title":"Identification and characterization of the unfolding transition state of chymotrypsin inhibitor 2 by molecular dynamics simulations.","volume":"257","author":"A Li","year":"1996","journal-title":"J Mol Biol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"13445","DOI":"10.1073\/pnas.0501773102","article-title":"Ensemble versus single-molecule protein unfolding.","volume":"102","author":"R Day","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"8473","DOI":"10.1073\/pnas.95.15.8473","article-title":"Synergy between simulation and experiment in describing the energy landscape of protein folding.","volume":"95","author":"AG Ladurner","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1126\/science.278.5345.1928","article-title":"\u201cNew view\u201d of protein folding reconciled with the old through multiple unfolding simulations.","volume":"278","author":"T Lazaridis","year":"1998","journal-title":"Science"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1006\/jmbi.1999.2942","article-title":"Mapping the interactions present in the transition state for unfolding\/folding of FKBP12.","volume":"291","author":"KF Fulton","year":"1999","journal-title":"J Mol Biol"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.jmb.2006.03.011","article-title":"The folding pathway of spectrin R17 from experiment and simulation: using experimentally validated MD simulations to characterize States hinted at by experiment.","volume":"359","author":"KA Scott","year":"2006","journal-title":"J Mol Biol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1016\/j.jmb.2007.06.023","article-title":"Unfolding Pathways of Goat \u03b1-Lactalbumin as Revealed in Multiple Alignment of Molecular Dynamics Trajectories.","volume":"371","author":"T Oroguchi","year":"2007","journal-title":"J Mol Biol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1006\/jmbi.1999.2843","article-title":"Analysis methods for comparison of multiple molecular dynamics trajectories: applications to protein unfolding pathways and denatured ensembles.","volume":"290","author":"SL Kazmirski","year":"1999","journal-title":"J Mol Biol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1126\/science.7618103","article-title":"First-principles calculation of the folding free energy of a three-helix bundle protein.","volume":"269","author":"EM Boczko","year":"1995","journal-title":"Science"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1146\/annurev.physchem.52.1.499","article-title":"From folding theories to folding proteins: a review and assessment of simulation studies of protein folding and unfolding.","volume":"52","author":"JE Shea","year":"2001","journal-title":"Annu Rev Phys Chem"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1002\/jcc.20289","article-title":"Scalable molecular dynamics with NAMD.","volume":"26","author":"JC Phillips","year":"2005","journal-title":"J Comput Chem"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"3586","DOI":"10.1021\/jp973084f","article-title":"All-atom empirical potential for molecular modeling and dynamics studies of proteins.","volume":"102","author":"AD MacKerell","year":"1998","journal-title":"Journal of Physical Chemistry B"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.jmb.2004.03.018","article-title":"The 0.83 A resolution crystal structure of alpha-lytic protease reveals the detailed structure of the active site and identifies a source of conformational strain.","volume":"338","author":"CN Fuhrmann","year":"2004","journal-title":"J Mol Biol"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1110\/ps.800101","article-title":"Enzyme specificity under dynamic control II: Principal component analysis of alpha-lytic protease using global and local solvent boundary conditions.","volume":"10","author":"N Ota","year":"2001","journal-title":"Protein Sci"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/nsb0197-10","article-title":"From Levinthal to pathways to funnels.","volume":"4","author":"KA Dill","year":"1997","journal-title":"Nat Struct Biol"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.jmb.2005.04.067","article-title":"The structure of the major transition state for folding of an FF domain from experiment and simulation.","volume":"350","author":"P Jemth","year":"2005","journal-title":"J Mol Biol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.1073\/pnas.0304825101","article-title":"Integrating folding kinetics and protein function: biphasic kinetics and dual binding specificity in a WW domain.","volume":"101","author":"J Karanicolas","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.jmb.2008.07.007","article-title":"Subdomain competition, cooperativity, and topological frustration in the folding of CheY.","volume":"382","author":"RD Hills Jr","year":"2008","journal-title":"J Mol Biol"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1093\/bioinformatics\/btl332","article-title":"THESEUS: maximum likelihood superpositioning and analysis of macromolecular structures.","volume":"22","author":"DL Theobald","year":"2006","journal-title":"Bioinformatics"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"e43","DOI":"10.1371\/journal.pcbi.0040043","article-title":"Accurate structural correlations from maximum likelihood superpositions.","volume":"4","author":"DL Theobald","year":"2008","journal-title":"Plos Computational Biology"},{"key":"ref34","article-title":"NMR Studies of Proteins: Assignments, Dynamics and Unfolding of alpha-lytic Protease, and Solution Structure of omega-conotoxin GVIA: University of California San Francisco","author":"JH Davis","year":"1996"},{"key":"ref35","article-title":"Thermodynamics, Kinetics and Landscapes in alpha-lytic Protease: A Role for Pro Regions and Kinetic Stability: University of California San Francisco","author":"SS Jaswal","year":"2000"},{"key":"ref36","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":"R Day","year":"2002","journal-title":"J Mol Biol"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1110\/ps.041226005","article-title":"Sensitivity of the folding\/unfolding transition state ensemble of chymotrypsin inhibitor 2 to changes in temperature and solvent.","volume":"14","author":"R Day","year":"2005","journal-title":"Protein Sci"},{"key":"ref38","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":"DAC Beck","year":"2007","journal-title":"Biophysical Journal"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0022-2836(02)00212-7","article-title":"Probing the energy landscape of protein folding\/unfolding transition states.","volume":"319","author":"D De Jong","year":"2002","journal-title":"Journal of Molecular Biology"},{"key":"ref40","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\u2020.","volume":"47","author":"ME McCully","year":"2008","journal-title":"Biochemistry"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1128\/jb.171.3.1320-1325.1989","article-title":"Analysis of prepro-alpha-lytic protease expression in Escherichia coli reveals that the pro region is required for activity.","volume":"171","author":"JL Silen","year":"1989","journal-title":"J Bacteriol"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1038\/2919","article-title":"Structure of alpha-lytic protease complexed with its pro region.","volume":"5","author":"NK Sauter","year":"1998","journal-title":"Nat Struct Biol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"12058","DOI":"10.1021\/bi980883v","article-title":"Pro region C-terminus:protease active site interactions are critical in catalyzing the folding of alpha-lytic protease.","volume":"37","author":"RJ Peters","year":"1998","journal-title":"Biochemistry"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1006\/jmbi.1996.0264","article-title":"Conservation and variability in the structures of serine proteinases of the chymotrypsin family.","volume":"258","author":"AM Lesk","year":"1996","journal-title":"J Mol Biol"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"9866","DOI":"10.1016\/S0021-9258(18)34152-8","article-title":"Refolding of bovine threonine-neochymotrypsinogen.","volume":"257","author":"CT Duda","year":"1982","journal-title":"J Biol Chem"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/S0021-9258(18)67428-9","article-title":"Independent refolding of domains in the pancreatic serine proteinases.","volume":"261","author":"JN Higaki","year":"1986","journal-title":"J Biol Chem"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"13212","DOI":"10.1021\/bi035409q","article-title":"Interdependent folding of the N- and C-terminal domains defines the cooperative folding of alpha-lytic protease.","volume":"42","author":"EL Cunningham","year":"2003","journal-title":"Biochemistry"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1016\/j.jmb.2007.02.077","article-title":"Comparison of proteolytic susceptibility in phosphoglycerate kinases from yeast and E-coli: Modulation of conformational ensembles without altering structure or stability.","volume":"368","author":"TA Young","year":"2007","journal-title":"J Mol Biol"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1016\/j.jmb.2007.02.091","article-title":"Energetics-based protein profiling on a proteomic scale: Identification of proteins resistant to proteolysis.","volume":"368","author":"C Park","year":"2007","journal-title":"J Mol Biol"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"L57","DOI":"10.1529\/biophysj.108.143388","article-title":"Coevolution of function and the folding landscape: correlation with density of native contacts.","volume":"95","author":"RD Hills Jr","year":"2008","journal-title":"Biophys J"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/prot.1","article-title":"The magnitude of the backbone conformational entropy change in protein folding.","volume":"25","author":"JA D'Aquino","year":"1996","journal-title":"Proteins"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1006\/jmbi.1998.1645","article-title":"Contact order, transition state placement and the refolding rates of single domain proteins.","volume":"277","author":"KW Plaxco","year":"1998","journal-title":"J Mol Biol"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1110\/ps.0302503","article-title":"Contact order revisited: influence of protein size on the folding rate.","volume":"12","author":"DN Ivankov","year":"2003","journal-title":"Protein Sci"},{"key":"ref54","article-title":"X-PLOR Version 3.1, A System for X-ray Crystallography and NMR.","author":"AT Brunger","year":"1992","journal-title":"The Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, Yale University"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1002\/jcc.10216","article-title":"Packing optimization for automated generation of complex system's initial configurations for molecular dynamics and docking.","volume":"24","author":"JM Mart\u00ednez","year":"2003","journal-title":"J Comput Chem"},{"key":"ref56","article-title":"Thermophysical Properties of Fluid Systems.","author":"EW Lemmon"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular-dynamics with coupling to an external bath.","volume":"81","author":"HJC Berendsen","year":"1984","journal-title":"Journal of Chemical Physics"},{"key":"ref58","article-title":"(2008) MATLAB. 7.6.0 ed."},{"key":"ref59","article-title":"The PyMOL Molecular Graphics System.","author":"WL DeLano","year":"2002"}],"container-title":["PLoS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pcbi.1000689","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,24]],"date-time":"2021-10-24T07:57:02Z","timestamp":1635062222000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1000689"}},"subtitle":[],"editor":[{"given":"B. Montgomery","family":"Pettitt","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2010,2,26]]},"references-count":59,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2010,2,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1000689","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,2,26]]}}}