{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:19:38Z","timestamp":1788430778556,"version":"build-2803163510"},"reference-count":68,"publisher":"American Chemical Society (ACS)","issue":"17","license":[{"start":{"date-parts":[[2015,4,10]],"date-time":"2015-04-10T00:00:00Z","timestamp":1428624000000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1P41 GM103712-01"],"award-info":[{"award-number":["1P41 GM103712-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006168","name":"National Nuclear Security Administration","doi-asserted-by":"publisher","award":["AC05-00OR22752"],"award-info":[{"award-number":["AC05-00OR22752"]}],"id":[{"id":"10.13039\/100006168","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents (\u201cbioscavengers\u201d) is an emerging prophylactic approach to diminish their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical\/molecular mechanical umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P\u2013F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily because of the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed \u03b2-propeller folds for more efficient degradation of OP compounds.<\/jats:p>","DOI":"10.1021\/jp410422c","type":"journal-article","created":{"date-parts":[[2014,4,10]],"date-time":"2014-04-10T20:20:47Z","timestamp":1397161247000},"page":"4479-4489","source":"Crossref","is-referenced-by-count":40,"title":["Hydrolysis\nof DFP and the Nerve Agent (\n                    <i>S<\/i>\n                    )-Sarin by DFPase\nProceeds along Two Different Reaction Pathways:\nImplications for Engineering Bioscavengers"],"prefix":"10.1021","volume":"118","author":[{"given":"Troy","family":"Wymore","sequence":"first","affiliation":[{"name":"Oak Ridge National Laboratory , , , ,","place":["Oak Ridge, Tennessee, United States, 37831-6309"]},{"name":"University of Tennessee , , , ,","place":["Knoxville, Tennessee, United States, 37996"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J.","family":"Field","sequence":"additional","affiliation":[{"name":"Institut de Biologie Structurale \u201cJean-Pierre Ebel\u201d , 41 rue Jules Horowitz , ,","place":["Grenoble Cedex 1, France, 38027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Langan","sequence":"additional","affiliation":[{"name":"Oak Ridge National Laboratory , , , ,","place":["Oak Ridge, Tennessee, United States, 37831-6309"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy C.","family":"Smith","sequence":"additional","affiliation":[{"name":"Oak Ridge National Laboratory , , , ,","place":["Oak Ridge, Tennessee, United States, 37831-6309"]},{"name":"University of Tennessee , , , ,","place":["Knoxville, Tennessee, United States, 37996"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry M.","family":"Parks","sequence":"additional","affiliation":[{"name":"Oak Ridge National Laboratory , , , ,","place":["Oak Ridge, Tennessee, United States, 37831-6309"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,4,10]]},"reference":[{"key":"2026090305563639600_cit1","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.bcp.2004.07.038","article-title":"Kinetic analysis of\ninteractions between human acetylcholinesterase, structurally different\norganophosphorus compounds and oximes","volume":"68","author":"Worek","year":"2004","journal-title":"Biochem.\nPharmacol."},{"key":"2026090305563639600_cit2","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.bcp.2009.08.027","article-title":"Crystal structures\nof oxime-bound fenamiphos-acetylcholinesterases: Reactivation involving\nflipping of the His447 ring to form a reactive Glu334\u2013His447\u2013oxime\ntriad","volume":"79","author":"Ho\u0308rnberg","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"2026090305563639600_cit3","doi-asserted-by":"crossref","first-page":"5295","DOI":"10.1039\/c1cc10787a","article-title":"First efficient\nuncharged reactivators for the dephosphylation of poisoned human acetylcholinesterase","volume":"47","author":"Mercey","year":"2011","journal-title":"Chem. Commun."},{"key":"2026090305563639600_cit4","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1002\/poc.778","article-title":"Stereochemistry\nand secondary reactions in the irreversible inhibition of serine hydrolases\nby organophosphorus compounds","volume":"17","author":"Kovach","year":"2004","journal-title":"J. Phys. Org.\nChem."},{"key":"2026090305563639600_cit5","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0003-9861(67)90006-9","article-title":"Ageing and\ndealkylation of soman\n(pinacolylmethylphosphono-fluoridate)-inactivated eel cholinesterase","volume":"121","author":"Michel","year":"1967","journal-title":"Arch. Biochem. Biophys."},{"key":"2026090305563639600_cit6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.toxlet.2011.04.006","article-title":"Evolution\nof and perspectives on therapeutic approaches to nerve agent poisoning","volume":"206","author":"Masson","year":"2011","journal-title":"Toxicol. Lett."},{"key":"2026090305563639600_cit7","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/469310a","article-title":"Chemical\nbiology: Catalytic detoxification","volume":"469","author":"Raushel","year":"2011","journal-title":"Nature"},{"key":"2026090305563639600_cit8","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.cbi.2013.06.012","article-title":"Progress in the development\nof enzyme-based nerve agent bioscavengers","volume":"206","author":"Nachon","year":"2013","journal-title":"Chem.\u2013Biol.\nInteract."},{"key":"2026090305563639600_cit9","doi-asserted-by":"crossref","first-page":"6463","DOI":"10.1021\/bi300811t","article-title":"Enzymes for the\nhomeland defense: Optimizing phosphotriesterase\nfor the hydrolysis of organophosphate nerve agents","volume":"51","author":"Tsai","year":"2012","journal-title":"Biochemistry"},{"key":"2026090305563639600_cit10","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1021\/cb4004892","article-title":"Engineering\nV-type nerve agents detoxifying enzymes using computationally focused\nlibraries","volume":"8","author":"Cherny","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"2026090305563639600_cit11","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.bbapap.2012.04.004","article-title":"Catalytic mechanisms for phosphotriesterases","volume":"1834","author":"Bigley","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"2026090305563639600_cit12","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.chembiol.2012.01.017","article-title":"Evolved\nstereoselective hydrolases for broad-spectrum G-type nerve agent detoxification","volume":"19","author":"Goldsmith","year":"2012","journal-title":"Chem. Biol."},{"key":"2026090305563639600_cit13","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/nchembio.510","article-title":"Directed evolution of hydrolases for prevention of G-type nerve agent\nintoxication","volume":"7","author":"Gupta","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"2026090305563639600_cit14","doi-asserted-by":"crossref","first-page":"12750","DOI":"10.1021\/ja061887n","article-title":"Binding of a\ndesigned substrate analogue to diisopropyl\nfluorophosphatase: Implications for the phosphotriesterase mechanism","volume":"128","author":"Blum","year":"2006","journal-title":"J. Am. Chem. Soc."},{"key":"2026090305563639600_cit15","doi-asserted-by":"crossref","first-page":"17226","DOI":"10.1021\/ja905444g","article-title":"Reversed enantioselectivity\nof diisopropyl fluorophosphatase against organophosphorus nerve agents\nby rational design","volume":"131","author":"Melzer","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"2026090305563639600_cit16","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/S0167-4838(01)00153-4","article-title":"Insights into\nthe reaction mechanism of the diisopropyl\nfluorophosphatase from Loligo vulgaris by means of\nkinetic studies, chemical modification and site-directed mutagenesis","volume":"1546","author":"Hartleib","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"2026090305563639600_cit17","doi-asserted-by":"crossref","first-page":"9022","DOI":"10.1021\/bi0500675","article-title":"Mutational and structural studies\nof the diisopropylfluorophosphatase from Loligo vulgaris shed new light on the catalytic mechanism of the enzyme","volume":"44","author":"Katsemi","year":"2005","journal-title":"Biochemistry"},{"key":"2026090305563639600_cit18","doi-asserted-by":"crossref","first-page":"6371","DOI":"10.1021\/bi047440d","article-title":"Structure\u2013reactivity studies of serum paraoxonase\nPON1 suggest that its native activity is lactonase","volume":"44","author":"Khersonsky","year":"2005","journal-title":"Biochemistry"},{"key":"2026090305563639600_cit19","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1107\/S0907444903016135","article-title":"Statistical analysis of crystallographic data obtained\nfrom squid ganglion DFPase at 0.85 A resolution","volume":"59","author":"Koepke","year":"2003","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"key":"2026090305563639600_cit20","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S0969-2126(01)00610-4","article-title":"Crystal structure\nof diisopropylfluorophosphatase from Loligo vulgaris","volume":"9","author":"Scharff","year":"2001","journal-title":"Structure"},{"key":"2026090305563639600_cit21","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1073\/pnas.0807842106","article-title":"Rapid determination of hydrogen positions\nand protonation states of diisopropyl fluorophosphatase by joint neutron\nand X-ray diffraction refinement","volume":"106","author":"Blum","year":"2009","journal-title":"Proc. Natl.\nAcad. Sci. U.S.A."},{"key":"2026090305563639600_cit22","doi-asserted-by":"crossref","first-page":"3082","DOI":"10.1002\/prot.23135","article-title":"The evolution of function in strictosidine synthase-like\nproteins","volume":"79","author":"Hicks","year":"2011","journal-title":"Proteins: Struct., Funct., Bioinf."},{"key":"2026090305563639600_cit23","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1107\/S0907444910034013","article-title":"Neutron\nstructure and mechanistic studies of diisopropyl fluorophosphatase\n(DFPase)","volume":"66","author":"Chen","year":"2010","journal-title":"Acta Crystallogr., Sect. D: Biol.\nCrystallogr."},{"key":"2026090305563639600_cit24","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nsmb767","article-title":"Structure\nand evolution\nof the serum paraoxonase family of detoxifying and anti-atherosclerotic\nenzymes","volume":"11","author":"Harel","year":"2004","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026090305563639600_cit25","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.bbapap.2012.02.007","article-title":"Differences\nin amino acid residues in the binding pockets dictate substrate specificities\nof mouse senescence marker protein-30, human paraoxonase 1, and squid\ndiisopropylfluorophosphatase","volume":"1824","author":"Belinskaya","year":"2012","journal-title":"Biochim. Biophys.\nActa"},{"key":"2026090305563639600_cit26","doi-asserted-by":"crossref","first-page":"308-1","DOI":"10.1186\/1756-0500-6-308","article-title":"Hydrogen atoms in protein structures:\nHigh-resolution X-ray diffraction structure of the DFPase","volume":"6","author":"Elias","year":"2013","journal-title":"BMC Res. Notes"},{"key":"2026090305563639600_cit27","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1021\/ar00166a001","article-title":"IUPAC recommendations for the representation of reaction\nmechanisms","volume":"22","author":"Guthrie","year":"1989","journal-title":"Acc. Chem. Res."},{"key":"2026090305563639600_cit28","doi-asserted-by":"crossref","first-page":"3252","DOI":"10.1021\/cr050287o","article-title":"Enzymatic mechanisms of phosphate\nand sulfate transfer","volume":"106","author":"Cleland","year":"2006","journal-title":"Chem. Rev."},{"key":"2026090305563639600_cit29","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0022-2836(76)90311-9","article-title":"Theoretical studies\nof enzymic reactions: dielectric,\nelectrostatic and steric stabilization of the carbonium ion in the\nreaction of lysozyme","volume":"103","author":"Warshel","year":"1976","journal-title":"J. Mol. Biol."},{"key":"2026090305563639600_cit30","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1021\/cr050293k","article-title":"Mechanisms\nand free energies of enzymatic reactions","volume":"106","author":"Gao","year":"2006","journal-title":"Chem.\nRev."},{"key":"2026090305563639600_cit31","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1002\/anie.200802019","article-title":"QM\/MM methods for biomolecular\nsystems","volume":"48","author":"Senn","year":"2009","journal-title":"Angew.\nChem., Int. Ed."},{"key":"2026090305563639600_cit32","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1021\/ci300363c","article-title":"Automation of the CHARMM general\nforce field (CGenFF) I: Bond perception and atom typing","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"2026090305563639600_cit33","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.1021\/ci3003649","article-title":"Automation of\nthe CHARMM general force field (CGenFF) II: Assignment of bonded parameters\nand partial atomic charges","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"2026090305563639600_cit34","first-page":"73","article-title":"The ORCA program\nsystem","volume":"2","author":"Neese","year":"2012","journal-title":"Wiley Interdiscip. Rev.: Comput. Mol.\nSci."},{"key":"2026090305563639600_cit35","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/jcc.21287","article-title":"CHARMM:\nThe biomolecular\nsimulation program","volume":"30","author":"Brooks","year":"2009","journal-title":"J. Comput. 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Phys."},{"key":"2026090305563639600_cit63","doi-asserted-by":"crossref","first-page":"5723","DOI":"10.1073\/pnas.0511225103","article-title":"Senescence\nmarker protein 30 functions\nas gluconolactonase in l-ascorbic acid biosynthesis, and\nits knockout mice are prone to scurvy","volume":"103","author":"Kondo","year":"2006","journal-title":"Proc.\nNatl. Acad. Sci. U.S.A."},{"key":"2026090305563639600_cit64","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.1190239","article-title":"Computational design of an enzyme catalyst\nfor a stereoselective bimolecular Diels\u2013Alder reaction","volume":"329","author":"Siegel","year":"2010","journal-title":"Science"},{"key":"2026090305563639600_cit65","doi-asserted-by":"crossref","first-page":"7649","DOI":"10.1074\/jbc.M512594200","article-title":"The histidine 115-histidine 134 dyad mediates the lactonase\nactivity of mammalian serum paraoxonases","volume":"281","author":"Khersonsky","year":"2006","journal-title":"J.\nBiol. 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