{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T09:07:57Z","timestamp":1775639277856,"version":"3.50.1"},"reference-count":67,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"D. E. Shaw Research"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are \u201ccryptic\u201d: When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)\u2014which performs its function by forming a PPI with its receptor\u2014without incorporating any prior structural information about the ligands\u2019 binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein\u2013small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2\u2013small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009817","type":"journal-article","created":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T13:53:26Z","timestamp":1646315606000},"page":"e1009817","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":51,"title":["How does a small molecule bind at a cryptic binding site?"],"prefix":"10.1371","volume":"18","author":[{"given":"Yibing","family":"Shan","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8973-1365","authenticated-orcid":true,"given":"Venkatesh P.","family":"Mysore","sequence":"additional","affiliation":[]},{"given":"Abba E.","family":"Leffler","sequence":"additional","affiliation":[]},{"given":"Eric T.","family":"Kim","sequence":"additional","affiliation":[]},{"given":"Shiori","family":"Sagawa","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8265-5761","authenticated-orcid":true,"given":"David E.","family":"Shaw","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"issue":"4","key":"pcbi.1009817.ref001","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.sbi.2005.06.001","article-title":"Protein-protein interactions in human disease","volume":"15","author":"D. P. Ryan","year":"2005","journal-title":"Curr Opin Struct Biol"},{"issue":"7172","key":"pcbi.1009817.ref002","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/nature06526","article-title":"Reaching for high-hanging fruit in drug discovery at protein-protein interfaces","volume":"450","author":"J. A. Wells","year":"2007","journal-title":"Nature"},{"issue":"1","key":"pcbi.1009817.ref003","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1006\/jmbi.1997.1234","article-title":"Analysis of protein-protein interaction sites using surface patches","volume":"272","author":"S. Jones","year":"1997","journal-title":"J Mol Biol"},{"issue":"4","key":"pcbi.1009817.ref004","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1021\/cr040409x","article-title":"Principles of protein-protein interactions: what are the preferred ways for proteins to interact?","volume":"108","author":"O. Keskin","year":"2008","journal-title":"Chemical Rev"},{"issue":"30","key":"pcbi.1009817.ref005","doi-asserted-by":"crossref","first-page":"4630","DOI":"10.2174\/138161212802651553","article-title":"Modulating protein-protein interactions: from structural determinants of binding to druggability prediction to application","volume":"18","author":"A. Metz","year":"2012","journal-title":"Curr Pharm Des"},{"issue":"4","key":"pcbi.1009817.ref006","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/nrd1343","article-title":"Small-molecule inhibitors of protein-protein interactions: progressing towards the dream","volume":"3","author":"M. R. Arkin","year":"2004","journal-title":"Nat Rev Drug Discov"},{"issue":"43","key":"pcbi.1009817.ref007","doi-asserted-by":"crossref","first-page":"14257","DOI":"10.1021\/jacs.6b05425","article-title":"Understanding cryptic pocket formation in protein targets by enhanced sampling simulations","volume":"138","author":"V. Oleinikovas","year":"2016","journal-title":"J Am Chem Soc"},{"issue":"1","key":"pcbi.1009817.ref008","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jmb.2006.03.021","article-title":"Computational sampling of a cryptic drug binding site in a protein receptor: explicit solvent molecular dynamics and inhibitor docking to p38 MAP kinase","volume":"359","author":"T. Frembgen-Kesner","year":"2006","journal-title":"J Mol Biol"},{"issue":"15","key":"pcbi.1009817.ref009","doi-asserted-by":"crossref","first-page":"E3416","DOI":"10.1073\/pnas.1711490115","article-title":"Exploring the structural origins of cryptic sites on proteins","volume":"115","author":"D. Beglov","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"pcbi.1009817.ref010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cbpa.2018.05.003","article-title":"Cryptic binding sites on proteins: definition, detection, and druggability","volume":"44","author":"S. Vajda","year":"2018","journal-title":"Curr Opin Chem Biol"},{"issue":"15","key":"pcbi.1009817.ref011","doi-asserted-by":"crossref","first-page":"3457","DOI":"10.1021\/jm070095g","article-title":"Transient pockets on protein surfaces involved in protein-protein interaction","volume":"50","author":"S. Eyrisch","year":"2007","journal-title":"J Med Chem"},{"issue":"4\u20136","key":"pcbi.1009817.ref012","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.cplett.2011.10.044","article-title":"Molecular modeling of the inhibition of protein\u2013protein interactions with small molecules: The IL2\u2013IL2R\u03b1 case","volume":"517","author":"S. Pieraccini","year":"2011","journal-title":"Chem Phys Lett"},{"issue":"1","key":"pcbi.1009817.ref013","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1021\/ci200322s","article-title":"Hot spots and transient pockets: predicting the determinants of small-molecule binding to a protein-protein interface","volume":"52","author":"A. Metz","year":"2012","journal-title":"J Chem Inf Model"},{"issue":"23","key":"pcbi.1009817.ref014","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1002\/jcc.23026","article-title":"Balancing target flexibility and target denaturation in computational fragment-based inhibitor discovery","volume":"33","author":"T. J. Foster","year":"2012","journal-title":"J Comput Chem"},{"issue":"3","key":"pcbi.1009817.ref015","doi-asserted-by":"crossref","first-page":"e1002951","DOI":"10.1371\/journal.pcbi.1002951","article-title":"Druggable protein interaction sites are more predisposed to surface pocket formation than the rest of the protein surface","volume":"9","author":"D. K. Johnson","year":"2013","journal-title":"PLoS Comput Biol"},{"issue":"7","key":"pcbi.1009817.ref016","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1021\/ct300117j","article-title":"Druggability assessment of allosteric proteins by dynamics simulations in the presence of probe molecules","volume":"8","author":"A. Bakan","year":"2012","journal-title":"J Chem Theory Comput"},{"issue":"3","key":"pcbi.1009817.ref017","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1747-0285.2010.01012.x","article-title":"Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach","volume":"76","author":"A. Ivetac","year":"2010","journal-title":"Chem Biol Drug Des"},{"issue":"9","key":"pcbi.1009817.ref018","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1073\/pnas.1417811112","article-title":"Discovery of multiple hidden allosteric sites by combining Markov state models and experiments","volume":"112","author":"G. R. Bowman","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"issue":"3","key":"pcbi.1009817.ref019","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1021\/acs.accounts.9b00613","article-title":"Investigating cryptic binding sites by molecular dynamics simulations","volume":"53","author":"A. Kuzmanic","year":"2020","journal-title":"Accounts Chem Res"},{"issue":"24","key":"pcbi.1009817.ref020","doi-asserted-by":"crossref","first-page":"9181","DOI":"10.1021\/ja202726y","article-title":"How does a drug molecule find its target binding site?","volume":"133","author":"Y. Shan","year":"2011","journal-title":"J Am Chem Soc"},{"issue":"4","key":"pcbi.1009817.ref021","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.cell.2012.02.063","article-title":"Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization","volume":"149","author":"Y. Shan","year":"2012","journal-title":"Cell"},{"issue":"3","key":"pcbi.1009817.ref022","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.cyto.2004.06.010","article-title":"Overview of interleukin-2 function, production and clinical applications","volume":"28","author":"S. L. Gaffen","year":"2004","journal-title":"Cytokine"},{"issue":"5","key":"pcbi.1009817.ref023","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.coi.2011.08.003","article-title":"IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation","volume":"23","author":"W. Liao","year":"2011","journal-title":"Curr Opin Immunol"},{"issue":"13","key":"pcbi.1009817.ref024","doi-asserted-by":"crossref","first-page":"3714","DOI":"10.1021\/ja034247i","article-title":"Discovery of a potent small molecule IL-2 inhibitor through fragment assembly","volume":"125","author":"A.C. Braisted","year":"2003","journal-title":"J Am Chem Soc"},{"issue":"42","key":"pcbi.1009817.ref025","doi-asserted-by":"crossref","first-page":"15422","DOI":"10.1073\/pnas.0607058103","article-title":"Hot-spot mimicry of a cytokine receptor by a small molecule","volume":"103","author":"C. D. Thanos","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"issue":"50","key":"pcbi.1009817.ref026","doi-asserted-by":"crossref","first-page":"15280","DOI":"10.1021\/ja0382617","article-title":"Potent small-molecule binding to a dynamic hot spot on IL-2","volume":"125","author":"C. D. Thanos","year":"2003","journal-title":"J Am Chem Soc"},{"key":"pcbi.1009817.ref027","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1063\/1.1740409","article-title":"High-temperature equation of state by a perturbation method. I. Nonpolar Gases","volume":"22","author":"R. W. Zwanzig","year":"1954","journal-title":"J Chem Phys"},{"key":"pcbi.1009817.ref028","first-page":"25","article-title":"Small-molecule inhibitors of IL-2\/IL-2R: lessons learned and applied","volume":"348","author":"C. G. M. Wilson","year":"2010","journal-title":"Curr Top Microbiol Immunol"},{"key":"pcbi.1009817.ref029","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1126\/science.1109745","article-title":"The structure of interleukin-2 complexed with its alpha receptor","volume":"308","author":"M. Rickert","year":"2005","journal-title":"Science"},{"issue":"9","key":"pcbi.1009817.ref030","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/nrd2082","article-title":"Drug-target residence time and its implications for lead optimization","volume":"5","author":"RA Copeland","year":"2006","journal-title":"Nat Rev Drug Discov"},{"issue":"7","key":"pcbi.1009817.ref031","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1021\/ja512751q","article-title":"Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field","volume":"137","author":"L. Wang","year":"2015","journal-title":"J Am Chem Soc"},{"issue":"35","key":"pcbi.1009817.ref032","doi-asserted-by":"crossref","first-page":"9535","DOI":"10.1021\/jp0217839","article-title":"Absolute binding free energies: a quantitative approach for their calculation","volume":"107","author":"S. Boresch","year":"2003","journal-title":"The Journal of Physical Chemistry B"},{"issue":"2","key":"pcbi.1009817.ref033","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/prot.20033","article-title":"Exploring protein native states and large-scale conformational changes with a modified generalized born model","volume":"55","author":"A. Onufriev","year":"2004","journal-title":"Proteins"},{"issue":"3","key":"pcbi.1009817.ref034","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/prot.340210302","article-title":"Funnels, pathways, and the energy landscape of protein folding: a synthesis","volume":"21","author":"J. D. Bryngelson","year":"1995","journal-title":"Proteins"},{"issue":"1","key":"pcbi.1009817.ref035","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0959-440X(02)00287-7","article-title":"Kinetic studies of protein-protein interactions","volume":"12","author":"G. Schreiber","year":"2002","journal-title":"Curr Opin Struct Biol"},{"issue":"10","key":"pcbi.1009817.ref036","doi-asserted-by":"crossref","first-page":"4244","DOI":"10.1073\/pnas.1815431116","article-title":"Atomic-level characterization of protein-protein association","volume":"116","author":"A. C. Pan","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"pcbi.1009817.ref037","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3410\/B3-19","article-title":"Conformational selection or induced fit? 50 years of debate resolved","volume":"3","author":"J. P. Changeux","year":"2011","journal-title":"F1000 Biol Rep"},{"issue":"11","key":"pcbi.1009817.ref038","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nchembio.232","article-title":"The role of dynamic conformational ensembles in biomolecular recognition","volume":"5","author":"D. D. Boehr","year":"2009","journal-title":"Nat Chem Biol"},{"issue":"10","key":"pcbi.1009817.ref039","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.tibs.2010.04.009","article-title":"Induced fit, conformational selection and independent dynamic segments: an extended view of binding events","volume":"35","author":"P. Csermely","year":"2010","journal-title":"Trends Biochem Sci"},{"issue":"22","key":"pcbi.1009817.ref040","doi-asserted-by":"crossref","first-page":"6449","DOI":"10.1021\/ja012498q","article-title":"Deuterium spin probes of side-chain dynamics in proteins. 2. Spectral density mapping and identification of nanosecond time-scale side-chain motions","volume":"124","author":"N. R. Skrynnikov","year":"2002","journal-title":"J Am Chem Soc"},{"issue":"3","key":"pcbi.1009817.ref041","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":"P. J. Hajduk","year":"2007","journal-title":"Nat Rev Drug Discov"},{"issue":"12","key":"pcbi.1009817.ref042","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/nchembio831","article-title":"Deconstructing fragment-based inhibitor discovery","volume":"2","author":"K. Babaoglu","year":"2006","journal-title":"Nat Chem Biol"},{"issue":"1\u20132","key":"pcbi.1009817.ref043","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.drudis.2006.11.011","article-title":"Drugs in other drugs: a new look at drugs as fragments","volume":"12","author":"M. G. Siegel","year":"2007","journal-title":"Drug Discov Today"},{"issue":"4","key":"pcbi.1009817.ref044","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1021\/jm061152t","article-title":"Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL","volume":"50","author":"M. Bruncko","year":"2007","journal-title":"J Med Chem"},{"issue":"5292","key":"pcbi.1009817.ref045","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1126\/science.274.5292.1531","article-title":"Discovering high-affinity ligands for proteins: SAR by NMR","volume":"274","author":"S. B. Shuker","year":"1996","journal-title":"Science"},{"issue":"2","key":"pcbi.1009817.ref046","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1021\/jm0495778","article-title":"Fragment-based lead discovery using X-ray crystallography","volume":"48","author":"M. J. Hartshorn","year":"2005","journal-title":"J Med Chem"},{"key":"pcbi.1009817.ref047","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/9780470122679.ch2","volume-title":"Advances in Enzymology and Related Areas of Molecular Biology","author":"D. E. Koshland","year":"1960"},{"key":"pcbi.1009817.ref048","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S0022-2836(65)80285-6","article-title":"On the nature of allosteric transitions: A plausible model","volume":"12","author":"J. Monod","year":"1965","journal-title":"J Mol Biol"},{"key":"pcbi.1009817.ref049","unstructured":"Schr\u00f6dinger Release 2018\u20132: Maestro, Schr\u00f6dinger, LLC, New York, NY, 2018."},{"issue":"8","key":"pcbi.1009817.ref050","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1002\/prot.22711","article-title":"Improved side-chain torsion potentials for the Amber ff99SB protein force field","volume":"78","author":"K. Lindorff-Larsen","year":"2010","journal-title":"Proteins"},{"issue":"3","key":"pcbi.1009817.ref051","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1002\/prot.21123","article-title":"Comparison of multiple Amber force fields and development of improved protein backbone parameters","volume":"65","author":"V. Hornak","year":"2006","journal-title":"Proteins"},{"issue":"26","key":"pcbi.1009817.ref052","doi-asserted-by":"crossref","first-page":"9004","DOI":"10.1021\/jp901540t","article-title":"Optimized molecular dynamics force fields applied to the helix-coil transition of polypeptides","volume":"113","author":"R. B. Best","year":"2009","journal-title":"J Phys Chem B"},{"issue":"12","key":"pcbi.1009817.ref053","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1002\/1096-987X(200009)21:12<1049::AID-JCC3>3.0.CO;2-F","article-title":"How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules?","volume":"21","author":"J. Wang","year":"2000","journal-title":"J Comput Chem"},{"key":"pcbi.1009817.ref054","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":"W. L. Jorgensen","year":"1983","journal-title":"J Chem Phys"},{"issue":"9","key":"pcbi.1009817.ref055","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general Amber force field","volume":"25","author":"J. Wang","year":"2004","journal-title":"J Comput Chem"},{"key":"pcbi.1009817.ref056","doi-asserted-by":"crossref","unstructured":"Shaw, D. E.; Dror, R. O.; Salmon, J. K.; Grossman, J. P.; Mackenzie, K. M.; Bank, J. A.; Young, C.; Deneroff, M. M.; Batson, B.; Bowers, K. J.; Chow, E.; Eastwood, M. P.; Ierardi, D. J.; Klepeis, J. L.; Kuskin, J. S.; Larson, R. H.; Lindorff-Larsen, K.; Maragakis, P.; Moraes, M. A.; Piana, S.; Shan, Y.; Towles, B. Millisecond-scale molecular dynamics simulations on Anton. Conference on High Performance Computing, Networking, Storage and Analysis (SC09) New York, NY: ACM, 2009.","DOI":"10.1145\/1654059.1654126"},{"key":"pcbi.1009817.ref057","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1103\/PhysRevA.31.1695","article-title":"A Canonical dynamics: Equilibrium phase-space distributions","volume":"31","author":"W. G. Hoover","year":"1985","journal-title":"Phys. Rev"},{"issue":"4","key":"pcbi.1009817.ref058","doi-asserted-by":"crossref","first-page":"046101","DOI":"10.1063\/1.2431176","article-title":"A common, avoidable source of error in molecular dynamics integrators","volume":"126","author":"R. A. Lippert","year":"2007","journal-title":"J. Chem. Phys"},{"key":"pcbi.1009817.ref059","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/1096-987X(20010415)22:5<501::AID-JCC1021>3.0.CO;2-V","article-title":"A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations","volume":"22","author":"V. Kr\u00e4utler","year":"2001","journal-title":"J. Comput. Chem"},{"key":"pcbi.1009817.ref060","doi-asserted-by":"crossref","first-page":"054101","DOI":"10.1063\/1.1839571","article-title":"Gaussian split Ewald: A fast Ewald mesh method for molecular simulation","volume":"122","author":"Y. Shan","year":"2005","journal-title":"J. Chem. Phys"},{"issue":"3","key":"pcbi.1009817.ref061","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1063\/1.463137","article-title":"Reversible multiple time scale molecular dynamics","volume":"97","author":"M. Tuckerman","year":"1992","journal-title":"J. Chem. Phys"},{"issue":"24","key":"pcbi.1009817.ref062","doi-asserted-by":"crossref","first-page":"7454","DOI":"10.1073\/pnas.1415846112","article-title":"Identifying localized changes in large systems: Change-point detection for biomolecular simulations","volume":"112","author":"Z. Fan","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"issue":"4 Pt. 2","key":"pcbi.1009817.ref063","doi-asserted-by":"crossref","first-page":"046705","DOI":"10.1103\/PhysRevE.80.046705","article-title":"Minimizing thermodynamic length to select intermediate states for free-energy calculations and replica-exchange simulations","volume":"80","author":"D. K. Shenfeld","year":"2009","journal-title":"Physical Review E"},{"issue":"7","key":"pcbi.1009817.ref064","doi-asserted-by":"crossref","first-page":"3372","DOI":"10.1021\/acs.jctc.7b00172","article-title":"Quantitative characterization of the binding and unbinding of millimolar drug fragments with molecular dynamics simulations","volume":"13","author":"A. C. Pan","year":"2017","journal-title":"Journal of chemical theory and computation"},{"key":"pcbi.1009817.ref065","unstructured":"Case, D. A.; Darden, T. A.; Cheatham, T. E., III.; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Merz, K. M.; Wang, B.; Pearlman, D. A.; Crowley, M.; Brozell, S.; Tsui, V; Gohlke, H.; Mongan, J.; Hornak, V.; Cui, G.; Beroza, P.; Schafmeister, C.; Caldwell, J. W.; Ross, W. S.; Kollman, P. A. Amber, version 8; University of California: San Francisco, 2004."},{"issue":"1","key":"pcbi.1009817.ref066","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: visual molecular dynamics","volume":"14","author":"W. Humphrey","year":"1996","journal-title":"J Mol Graph"},{"issue":"23","key":"pcbi.1009817.ref067","doi-asserted-by":"crossref","first-page":"3276","DOI":"10.1093\/bioinformatics\/btr550","article-title":"MDpocket: open-source cavity detection and characterization on molecular dynamics trajectories","volume":"27","author":"P. Schmidtke","year":"2011","journal-title":"Bioinformatics"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009817","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T05:46:28Z","timestamp":1700286388000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009817"}},"subtitle":[],"editor":[{"given":"Anna R","family":"Panchenko","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,3,3]]},"references-count":67,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009817","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.03.31.437917","asserted-by":"object"}],"has-review":[{"id-type":"doi","id":"10.3410\/f.741752774.793592740","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,3]]}}}