{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T07:18:05Z","timestamp":1777619885413,"version":"3.51.4"},"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"2","content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1002002","type":"journal-article","created":{"date-parts":[[2011,2,3]],"date-time":"2011-02-03T21:37:27Z","timestamp":1296769047000},"page":"e1002002","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":107,"title":["The Free Energy Landscape of Small Molecule Unbinding"],"prefix":"10.1371","volume":"7","author":[{"given":"Danzhi","family":"Huang","sequence":"first","affiliation":[]},{"given":"Amedeo","family":"Caflisch","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2011,2,3]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/nrd2220","article-title":"A decade of fragment-based drug design: strategic advances and lessons learned.","volume":"6","author":"PJ Hajduk","year":"2007","journal-title":"Nat Rev Drug Discov"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"3661","DOI":"10.1021\/jm8000373","article-title":"Recent developments in fragment-based drug discovery.","volume":"51","author":"M Congreve","year":"2008","journal-title":"J Med Chem"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1126\/science.1096361","article-title":"The many roles of computation in drug discovery.","volume":"303","author":"WL Jorgensen","year":"2004","journal-title":"Science"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/jmr.981","article-title":"Library screening by fragment-based docking.","volume":"23","author":"D Huang","year":"2010","journal-title":"J Mol Recognit"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"e1000435","DOI":"10.1371\/journal.pcbi.1000435","article-title":"Computational fragment-based binding site identification by ligand competitive saturation.","volume":"5","author":"O Guvench","year":"2009","journal-title":"PLoS Comput Biol"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1021\/jm801385d","article-title":"Binding site detection and druggability index from first principles.","volume":"52","author":"J Seco","year":"2009","journal-title":"J Med Chem"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"4860","DOI":"10.1021\/jm900448m","article-title":"Flaviviral protease inhibitors identified by fragment-based library docking into a structure generated by molecular dynamics.","volume":"52","author":"D Ekonomiuk","year":"2009","journal-title":"J Med Chem"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.chembiol.2009.12.011","article-title":"Toward the rational design of p53-stabilizing drugs: probing the surface of the oncogenic Y220C mutant.","volume":"17","author":"N Basse","year":"2010","journal-title":"Chem Biol"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1110\/ps.041280705","article-title":"Change of the unbinding mechanism upon a mutation: A molecular dynamics study of an antibody-hapten complex.","volume":"14","author":"R Curcio","year":"2005","journal-title":"Protein Science"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"7361","DOI":"10.1021\/ja100259r","article-title":"Single-molecule pulling simulations can discern active from inactive enzyme inhibitors.","volume":"132","author":"F Colizzi","year":"2010","journal-title":"J Am Chem Soc"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.jmb.2004.06.063","article-title":"The protein folding network.","volume":"342","author":"F Rao","year":"2004","journal-title":"J Mol Biol"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"6571","DOI":"10.1021\/jp037421y","article-title":"Describing protein folding kinetics by molecular dynamics simulations. 1. Theory.","volume":"108","author":"W Swope","year":"2004","journal-title":"J Phys Chem B"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"12689","DOI":"10.1021\/jp060039b","article-title":"One-dimensional free-energy profiles of complex systems: Progress variables that preserve the barriers.","volume":"110","author":"SV Krivov","year":"2006","journal-title":"J Phys Chem B"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.sbi.2006.01.002","article-title":"Network and graph analyses of folding free energy surfaces.","volume":"16","author":"A Caflisch","year":"2006","journal-title":"Curr Opin Struct Biol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"155101","DOI":"10.1063\/1.2714538","article-title":"Automatic discovery of metastable states for the construction of Markov models of macromolecular conformational dynamics.","volume":"126","author":"JD Chodera","year":"2007","journal-title":"J Chem Phys"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"155102","DOI":"10.1063\/1.2714539","article-title":"Hierarchical analysis of conformational dynamics in biomolecules: Transition networks of metastable states.","volume":"126","author":"F No\u00e9","year":"2007","journal-title":"J Chem Phys"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.sbi.2008.01.008","article-title":"Transition networks for modeling the kinetics of conformational changes in macromolecules.","volume":"18","author":"F No\u00e9","year":"2008","journal-title":"Curr Opin Struct Biol"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"6057","DOI":"10.1021\/jp0761665","article-title":"Coarse Master Equations for Peptide Folding Dynamics.","volume":"112","author":"N Buchete","year":"2008","journal-title":"J Phys Chem B"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"205102","DOI":"10.1063\/1.3139063","article-title":"Reactive flux and folding pathways in network models of coarse-grained protein dynamics.","volume":"130","author":"A Berezhkovskii","year":"2009","journal-title":"J Chem Phys"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1002\/prot.21565","article-title":"Kinetic analysis of molecular dynamics simulations reveals changes in the denatured state and switch of folding pathways upon single-point mutation of a <italic>\u03b2<\/italic>-sheet miniprotein.","volume":"70","author":"S Muff","year":"2008","journal-title":"Proteins: Structure, Function, and Bioinformatics"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"8701","DOI":"10.1021\/jp711864r","article-title":"One-dimensional barrier preserving free-energy projections of a beta-sheet miniprotein: New insights into the folding process.","volume":"112","author":"SV Krivov","year":"2008","journal-title":"J Phys Chem B"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"125104","DOI":"10.1063\/1.3099705","article-title":"Identification of the protein folding transition state from molecular dynamics trajectories.","volume":"130","author":"S Muff","year":"2009","journal-title":"J Chem Phys"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"9588","DOI":"10.1073\/pnas.0712099105","article-title":"<italic>\u03b1<\/italic>-helix folding in the presence of structural constraints.","volume":"105","author":"JA Ihalainen","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"4435","DOI":"10.1021\/jp810431s","article-title":"Bulky side chains and non-native salt bridges slow down the folding of a cross-linked helical peptide: a combined molecular dynamics and time-resolved infrared spectroscopy study.","volume":"113","author":"B Paoli","year":"2009","journal-title":"J Phys Chem B"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1021\/jp910216j","article-title":"Slow Folding of Cross-Linked alpha-Helical Peptides Due to Steric Hindrance.","volume":"114","author":"B Paoli","year":"2010","journal-title":"J Phys Chem B"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"17747","DOI":"10.1073\/pnas.0605580103","article-title":"Understanding ensemble protein folding at atomic detail.","volume":"103","author":"IA Hubner","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1016\/j.bpj.2009.06.047","article-title":"How does a simplified-sequence protein fold?","volume":"97","author":"E Guarnera","year":"2009","journal-title":"Biophys J"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"10890","DOI":"10.1073\/pnas.1003962107","article-title":"Protein folded states are kinetic hubs.","volume":"107","author":"GR Bowman","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref29","first-page":"3728","article-title":"Free Energy Surfaces from Single-Distance Information.","author":"P Schuetz","year":"2010"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1006\/jmbi.1999.3411","article-title":"X-ray structures of small ligand-FKBP complexes provide an estimate for hydrophobic interaction energies.","volume":"295","author":"P Burkhard","year":"2000","journal-title":"J Mol Biol"},{"key":"ref31","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":"ref32","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":"EA MacKerell Jr","year":"1998","journal-title":"J Phys Chem B"},{"key":"ref33","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":"WL Jorgensen","year":"1983","journal-title":"J Chem Phys"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields.","volume":"31","author":"K Vanommeslaeghe","year":"2010","journal-title":"J Comput Chem"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: an Nlog(N) method for Ewald sums in large systems.","volume":"98","author":"T Darden","year":"1993","journal-title":"J Chem Phys"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"4613","DOI":"10.1063\/1.470648","article-title":"Constant pressure molecular dynamics simulation: the Langevin piston method.","volume":"103","author":"S Feller","year":"1995","journal-title":"J Chem Phys"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/jcc.21287","article-title":"CHARMM: the biomolecular simulation program.","volume":"30","author":"BR Brooks","year":"2009","journal-title":"J Comput Chem"},{"key":"ref38","first-page":"2625","article-title":"Wordom: a program for efficient analysis of molecular dynamics simulations","volume":"23","author":"M Seeber","year":"2007"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1002\/spe.4380211102","article-title":"Graph drawing by force-directed placement.","volume":"21","author":"TMJ Fruchterman","year":"1991","journal-title":"Software - Practice and Experience"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"13841","DOI":"10.1073\/pnas.0800228105","article-title":"Diffusive reaction dynamics on invariant free energy profiles.","volume":"105","author":"SV Krivov","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref41","doi-asserted-by":"crossref","DOI":"10.1145\/565196.565199","article-title":"Stochastic roadmap simulation: An efficient representation and algorithm for analyzing molecular motion.","author":"M Apaydin","year":"2002"},{"key":"ref42","article-title":"Amyloid fibril formation is under kinetic control.","author":"R Pellarin","journal-title":"J Am Chem Soc"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"184901","DOI":"10.1063\/1.1893753","article-title":"Estimation of protein folding probability from equilibrium simulations.","volume":"122","author":"F Rao","year":"2005","journal-title":"J Chem Phys"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/BF01877232","article-title":"Protein hydration studied with homonuclear 3D 1H NMR experiments.","volume":"1","author":"G Otting","year":"1991","journal-title":"J Biomol NMR"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"18461","DOI":"10.1073\/pnas.0707647104","article-title":"Mapping hydration dynamics around a protein surface.","volume":"104","author":"L Zhang","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1006\/jmbi.1994.1356","article-title":"Solution structure and dynamics of PEC-60, a protein of the Kazal type inhibitor family, determined by nuclear magnetic resonance spectroscopy.","volume":"239","author":"E Liepinsh","year":"1994","journal-title":"J Mol Biol"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/0014-5793(95)00459-M","article-title":"Interaction of urea with an unfolded protein. The DNA-binding domain of the 434-repressor.","volume":"366","author":"V Dotsch","year":"1995","journal-title":"FEBS Lett"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.ab.2003.10.025","article-title":"A Biacore biosensor method for detailed kinetic binding analysis of small molecule inhibitors of p38alpha mitogen-activated protein kinase.","volume":"325","author":"D Casper","year":"2004","journal-title":"Anal Biochem"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1006\/abio.1996.0067","article-title":"Competition BIAcore for measuring true affinities: large differences from values determined from binding kinetics.","volume":"234","author":"L Nieba","year":"1996","journal-title":"Anal Biochem"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1023\/A:1007930623000","article-title":"Ligand binding affinity prediction by linear interaction energy methods.","volume":"12","author":"T Hansson","year":"1998","journal-title":"J Comput-Aided Mol Design"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1093\/protein\/7.3.385","article-title":"A new method for predicting binding affinity in computer-aided drug design.","volume":"7","author":"J \u00c5qvist","year":"1994","journal-title":"Protein Engineering"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1021\/jm960684e","article-title":"Binding affinities for sulfonamide inhibitors with human thrombin using monte carlo simulations with a linear response method.","volume":"40","author":"DK Jones-Hertzog","year":"1996","journal-title":"J Med Chem"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1017\/S0033583500005333","article-title":"Calculations of electrostatic interactions in biological-systems and in solutions.","volume":"17","author":"A Warshel","year":"1984","journal-title":"Q Rev Biophys"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"4683","DOI":"10.1021\/j100374a057","article-title":"Molecular basis for the Born model of ion solvation.","volume":"94","author":"B Roux","year":"1990","journal-title":"J Phys Chem"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"4280","DOI":"10.1021\/jm800242q","article-title":"Is quantum mechanics necessary for predicting binding free energy?","volume":"51","author":"T Zhou","year":"2008","journal-title":"J Med Chem"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.jmb.2007.06.002","article-title":"Predicting absolute ligand binding free energies to a simple model site.","volume":"371","author":"D Mobley","year":"2007","journal-title":"J Mol Biol"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.jmb.2009.09.049","article-title":"Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site.","volume":"394","author":"SE Boyce","year":"2009","journal-title":"J Mol Biol"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.str.2009.02.010","article-title":"Binding of Small-Molecule Ligands to Proteins.","volume":"17","author":"D Mobley","year":"2009","journal-title":"Structure"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1063\/1.436049","article-title":"Statistical mechanics of isomerization dynamics in liquids and the transition state approximation.","volume":"68","author":"D Chandler","year":"1978","journal-title":"J Chem Phys"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1063\/1.475393","article-title":"On the transition coordinate for protein folding.","volume":"108","author":"R Du","year":"1998","journal-title":"J Chem Phys"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1021\/ja01607a027","article-title":"A correlation of reaction rates.","volume":"77","author":"GS Hammond","year":"1955","journal-title":"J Am Chem Soc"},{"key":"ref62","doi-asserted-by":"crossref","first-page":"13656","DOI":"10.1021\/bi00041a047","article-title":"Movement of the position of the transition state in protein folding.","volume":"34","author":"A Matouschek","year":"1995","journal-title":"Biochemistry"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"19011","DOI":"10.1073\/pnas.0905466106","article-title":"Constructing the equilibrium ensemble of folding pathways from short off-equilibrium simulations.","volume":"106","author":"F No\u00e9","year":"2009","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1021\/ja9090353","article-title":"Molecular Simulation of ab Initio Protein Folding for a Millisecond Folder NTL9 (1- 39).","volume":"132","author":"V Voelz","year":"2010","journal-title":"J Am Chem Soc"},{"key":"ref65","doi-asserted-by":"crossref","first-page":"6433","DOI":"10.1021\/jm9009444","article-title":"Structure-based optimization of potent and selective inhibitors of the tyrosine kinase Ephb4.","volume":"52","author":"K Lafleur","year":"2009","journal-title":"J Med Chem"},{"key":"ref66","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1107\/S0108767388010128","article-title":"On the orthogonal transformation used for structural comparisons.","volume":"45","author":"SK Kearsley","year":"1989","journal-title":"Acta Crystallographica Section A"}],"container-title":["PLoS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pcbi.1002002","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T20:46:39Z","timestamp":1712177199000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1002002"}},"subtitle":[],"editor":[{"given":"Bert L.","family":"de Groot","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2011,2,3]]},"references-count":66,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2011,2,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1002002","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,2,3]]}}}