{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:21:31Z","timestamp":1788351691439,"version":"build-2803163510"},"reference-count":72,"publisher":"American Chemical Society (ACS)","issue":"20","license":[{"start":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T00:00:00Z","timestamp":1589414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006151","name":"Basic Energy Sciences","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100006151","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005031","name":"Bhabha Atomic Research Centre","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100005031","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>HIV-1 protease is indispensable for virus propagation and an important therapeutic target for antiviral inhibitors to treat AIDS. As such inhibitors are transition-state mimics, a detailed understanding of the enzyme mechanism is crucial for the development of better anti-HIV drugs. Here, we used room-temperature joint X-ray\/neutron crystallography to directly visualize hydrogen atoms and map hydrogen bonding interactions in a protease complex with peptidomimetic inhibitor KVS-1 containing a reactive nonhydrolyzable ketomethylene isostere, which, upon reacting with the catalytic water molecule, is converted into a tetrahedral intermediate state, KVS-1TI. We unambiguously determined that the resulting tetrahedral intermediate is an oxyanion, rather than the gem-diol, and both catalytic aspartic acid residues are protonated. The oxyanion tetrahedral intermediate appears to be unstable, even though the negative charge on the oxyanion is delocalized through a strong n \u2192 \u03c0* hyperconjugative interaction into the nearby peptidic carbonyl group of the inhibitor. To better understand the influence of the ketomethylene isostere as a protease inhibitor, we have also examined the protease structure and binding affinity with keto-darunavir (keto-DRV), which similar to KVS-1 includes the ketomethylene isostere. We show that keto-DRV is a significantly less potent protease inhibitor than DRV. These findings shed light on the reaction mechanism of peptide hydrolysis catalyzed by HIV-1 protease and provide valuable insights into further improvements in the design of protease inhibitors.<\/jats:p>","DOI":"10.1021\/acsomega.0c00835","type":"journal-article","created":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T11:58:34Z","timestamp":1589457514000},"page":"11605-11617","source":"Crossref","is-referenced-by-count":10,"title":["Visualizing Tetrahedral Oxyanion Bound in HIV-1 Protease Using\nNeutrons: Implications for the Catalytic Mechanism and Drug Design"],"prefix":"10.1021","volume":"5","author":[{"given":"Mukesh","family":"Kumar","sequence":"first","affiliation":[{"name":"Bhabha Atomic Research Centre , , Trombay, ,","place":["Mumbai, India, 400085"]},{"name":"Homi Bhabha National Institute , Anushaktinagar , ,","place":["Mumbai, India, 400094"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3194-1378","authenticated-orcid":true,"given":"Kalyaneswar","family":"Mandal","sequence":"additional","affiliation":[{"name":"University of Chicago , , , ,","place":["Chicago, Illinois, United States, 60637"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6412-4358","authenticated-orcid":true,"given":"Matthew P.","family":"Blakeley","sequence":"additional","affiliation":[{"name":"Institut Laue\u2212Langevin , , ,","place":["Grenoble, France, 38000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1969-2652","authenticated-orcid":true,"given":"Troy","family":"Wymore","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen B. H.","family":"Kent","sequence":"additional","affiliation":[{"name":"University of Chicago , , , ,","place":["Chicago, Illinois, United States, 60637"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Louis","sequence":"additional","affiliation":[{"name":"National Institutes of Health, DHHS , , , ,","place":["Bethesda, Maryland, United States, 20892-0520"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Das","sequence":"additional","affiliation":[{"name":"Bhabha Atomic Research Centre , , Trombay, ,","place":["Mumbai, India, 400085"]},{"name":"Homi Bhabha National Institute , Anushaktinagar , ,","place":["Mumbai, India, 400094"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4459-9142","authenticated-orcid":true,"given":"Andrey","family":"Kovalevsky","sequence":"additional","affiliation":[{"name":"Oak Ridge National Laboratory , , , ,","place":["Oak Ridge, Tennessee, United States, 37830"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,5,14]]},"reference":[{"key":"2026090207591285800_cit1","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/nrmicro2747","article-title":"The Structural Biology of HIV-1: Mechanistic and Therapeutic\nInsights","volume":"10","author":"Engelman","year":"2012","journal-title":"Nat. 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Pharmacol."},{"key":"2026090207591285800_cit5","doi-asserted-by":"publisher","first-page":"5172","DOI":"10.1021\/acs.jmedchem.5b01697","article-title":"Recent Progress\nin the Development of HIV-1 Protease Inhibitors for the Treatment\nof HIV\/AIDS","volume":"59","author":"Ghosh","year":"2016","journal-title":"J. Med. Chem."},{"key":"2026090207591285800_cit6","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/j.ejmech.2017.07.044","article-title":"Design Strategies\nin the Prodrugs of HIV-1 Protease Inhibitors to Improve the Pharmaceutical\nProperties","volume":"139","author":"Subbaiah","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"2026090207591285800_cit7","doi-asserted-by":"crossref","first-page":"273","DOI":"10.18388\/pb.2016_26","article-title":"Tackling the Problem\nof HIV Drug Resistance","volume":"62","author":"Weber","year":"2016","journal-title":"Postepy Biochem."},{"key":"2026090207591285800_cit8","doi-asserted-by":"publisher","first-page":"37","DOI":"10.2174\/1568005024605837","article-title":"Defining HIV-1\nProtease Substrate Selectivity","volume":"2","author":"Beck","year":"2002","journal-title":"Curr. 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Use of\npH Rate Studies and Solvent Kinetic Isotope Effects to Elucidate Details\nof Chemical Mechanism","volume":"30","author":"Hyland","year":"1991","journal-title":"Biochemistry"},{"key":"2026090207591285800_cit16","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1021\/ar000184m","article-title":"Follow the Protons: A Low-Barrier Hydrogen Bond Unifies\nthe Mechanisms of the Aspartic Proteases","volume":"34","author":"Northrop","year":"2001","journal-title":"Acc.\nChem. Res."},{"key":"2026090207591285800_cit17","doi-asserted-by":"publisher","first-page":"6543","DOI":"10.1073\/pnas.1202808109","article-title":"Transition States of Native and Drug-Resistant\nHIV-1 Protease are the Same","volume":"109","author":"Kipp","year":"2012","journal-title":"Proc. Natl. Acad.\nSci. U.S.A."},{"key":"2026090207591285800_cit18","doi-asserted-by":"publisher","first-page":"5887","DOI":"10.1039\/c2ob25569c","article-title":"Ionization State\nof the Catalytic Dyad Asp25\/25\u2019 in the HIV-1 Protease: NMR\nStudies of Site-Specifically 13C Labelled HIV-1 Protease\nPrepared by Total Chemical Synthesis","volume":"10","author":"Torbeev","year":"2012","journal-title":"Org. Biomol.\nChem."},{"key":"2026090207591285800_cit19","doi-asserted-by":"publisher","first-page":"12380","DOI":"10.1021\/bi00097a015","article-title":"Use of\nNitrogen-15 Kinetic Isotope Effects to Elucidate Details of the Chemical\nMechanism of Human Immunodeficiency Virus 1 Protease","volume":"32","author":"Rodriguez","year":"1993","journal-title":"Biochemistry"},{"key":"2026090207591285800_cit20","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1093\/proeng\/gzg027","article-title":"Close Pairs\nof Carboxylates: a Possibility of Multicenter Hydrogen Bonds in Proteins","volume":"16","author":"Torshin","year":"2003","journal-title":"Protein Eng."},{"key":"2026090207591285800_cit21","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1002\/(sici)1097-0134(20000401)39:1&lt;26::aid-prot3&gt;3.0.co;2-n","article-title":"Conformational Flexibility\nof the Catalytic Asp Dyad in HIV-1 Protease: an Ab Initio Study on\nthe Free Enzyme","volume":"39","author":"Piana","year":"2000","journal-title":"Proteins: Struct., Funct.,\nGenet."},{"key":"2026090207591285800_cit22","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1021\/ct600200s","article-title":"The Low-Barrier\nDouble-Well Potential of the O\u03b41-H-O\u03b41 Hydrogen Bond in\nUnbound HIV Protease: a QM\/MM Characterization","volume":"2","author":"Porter","year":"2006","journal-title":"J. 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Soc."},{"key":"2026090207591285800_cit25","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/s0022-2836(02)00301-7","article-title":"Role of Conformational Fluctuations\nin the Enzymatic Reaction of HIV-1 Protease","volume":"319","author":"Piana","year":"2002","journal-title":"J. Mol. Biol."},{"key":"2026090207591285800_cit26","doi-asserted-by":"publisher","first-page":"11139","DOI":"10.1021\/jp037651c","article-title":"Reaction Mechanism of HIV-1 Protease by Hybrid Car-Parrinello\/Classical\nMD Simulations","volume":"108","author":"Piana","year":"2004","journal-title":"J. Phys. Chem. B"},{"key":"2026090207591285800_cit27","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1110\/ps.03372304","article-title":"The Role of Hydrogen Bonding in the\nEnzymatic Reaction Catalyzed by HIV-1 Protease","volume":"13","author":"Trylska","year":"2004","journal-title":"Protein Sci."},{"key":"2026090207591285800_cit28","doi-asserted-by":"publisher","first-page":"7709","DOI":"10.1021\/bi060131y","article-title":"Catalysis\nand Linear Free Energy Relationships in Aspartic Proteases","volume":"45","author":"Bjelic","year":"2006","journal-title":"Biochemistry"},{"key":"2026090207591285800_cit29","doi-asserted-by":"publisher","first-page":"8545","DOI":"10.1021\/jp200565w","article-title":"Understanding\nthe HIV-1 Protease Reactivity with DFT: What Do We Gain from Recent\nFunctionals?","volume":"115","author":"Garrec","year":"2011","journal-title":"J. Phys. Chem. B"},{"key":"2026090207591285800_cit30","doi-asserted-by":"publisher","first-page":"5617","DOI":"10.1021\/acscatal.5b00759","article-title":"Enzymatic Flexibility and Reaction Rate: a QM\/MM Study\nof HIV-1 Protease","volume":"5","author":"Ribeiro","year":"2015","journal-title":"ACS Catal."},{"key":"2026090207591285800_cit31","doi-asserted-by":"publisher","first-page":"16283","DOI":"10.1021\/jacs.6b06856","article-title":"Dynamic and Electrostatic\nEffects on the Reaction Catalyzed by HIV-1 Protease","volume":"138","author":"Krzeminska","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"2026090207591285800_cit32","doi-asserted-by":"publisher","first-page":"11200","DOI":"10.1002\/chem.201802035","article-title":"Using the Relative Energy Gradient\nMethod with Interacting Quantum Atoms to Determine the Reaction Mechanism\nand Catalytic Effects in the Peptide Hydrolysis in HIV-1 Protease","volume":"24","author":"Thacker","year":"2018","journal-title":"Chem.\u2500Eur. J."},{"key":"2026090207591285800_cit33","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1021\/ct5008845","article-title":"Computing the Role of Near Attack Conformations in\nan Enzyme-Catalyzed Nucleophilic Bimolecular Reaction","volume":"11","author":"Sadiq","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"2026090207591285800_cit34","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1007\/s11224-018-1251-9","article-title":"Unraveling the Concerted Catalytic Mechanism of the\nHuman Immunodeficiency Virus Type 1 (HIV-1) Protease: a Hybrid QM\/MM\nStudy","volume":"30","author":"Lawal","year":"2019","journal-title":"Struct. Chem."},{"key":"2026090207591285800_cit35","doi-asserted-by":"publisher","first-page":"11867","DOI":"10.1021\/ja00153a008","article-title":"Selectivity in the Inhibition of HIV and FIV Protease:\nInhibitory and Mechanistic Studies of Pyrrolidine-Containing \u03b1-Keto\nAmide and Hydroxyethyleneamine Core Structures","volume":"117","author":"Slee","year":"1995","journal-title":"J. Am. Chem. Soc."},{"key":"2026090207591285800_cit36","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1006\/jmbi.1996.0026","article-title":"Inhibition and Catalytic Mechanism of HIV-1 Aspartic\nProtease","volume":"255","author":"Silva","year":"1996","journal-title":"J. Mol. Biol."},{"key":"2026090207591285800_cit37","doi-asserted-by":"publisher","first-page":"14854","DOI":"10.1021\/bi700822g","article-title":"Caught\nin the Act: the 1.5 \u00c5 Resolution Crystal Structures of the HIV-1\nProtease and the I54V Mutant Reveal a Tetrahedral Reaction Intermediate","volume":"46","author":"Kovalevsky","year":"2007","journal-title":"Biochemistry"},{"key":"2026090207591285800_cit38","doi-asserted-by":"publisher","first-page":"6366","DOI":"10.1021\/ja100002b","article-title":"X-ray Snapshot of\nHIV-1 Protease in Action: Observation of Tetrahedral Intermediate\nand Short Ionic Hydrogen Bond SIHB with Catalytic Aspartate","volume":"132","author":"Das","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"2026090207591285800_cit39","doi-asserted-by":"publisher","first-page":"7726","DOI":"10.1021\/bi3008092","article-title":"Capturing\nthe Reaction Pathway in Near-Atomic-Resolution Crystal Structures\nof HIV-1 Protease","volume":"51","author":"Shen","year":"2012","journal-title":"Biochemistry"},{"key":"2026090207591285800_cit40","doi-asserted-by":"publisher","first-page":"596","DOI":"10.3390\/molecules22040596","article-title":"Neutron Crystallography for the Study\nof Hydrogen Bonds in Macromolecules","volume":"22","author":"Oksanen","year":"2017","journal-title":"Molecules"},{"key":"2026090207591285800_cit41","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1107\/s2059798318017503","article-title":"Neutron Scattering\nin the Biological Sciences: Progress and Prospects","volume":"74","author":"Ashkar","year":"2018","journal-title":"Acta Crystallogr., Sect. D: Struct. Biol."},{"key":"2026090207591285800_cit42","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1107\/s0907444909011548","article-title":"Generalized\nX-ray and Neutron Crystallographic Analysis: More Accurate and Complete\nStructures for Biological Macromolecules","volume":"65","author":"Adams","year":"2009","journal-title":"Acta\nCrystallogr., Sect. D: Biol. Crystallogr."},{"key":"2026090207591285800_cit43","doi-asserted-by":"publisher","first-page":"4554","DOI":"10.1016\/j.bmcl.2008.07.039","article-title":"Crystal\nStructure of Chemically Synthesized HIV-1 Protease and a Ketomethylene\nIsostere Inhibitor Based on the p2\/NC Cleavage Site","volume":"18","author":"Torbeev","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090207591285800_cit44","doi-asserted-by":"publisher","first-page":"20982","DOI":"10.1073\/pnas.1111202108","article-title":"Protein\nConformational Dynamics in the Mechanism of HIV-1 Protease Catalysis","volume":"108","author":"Torbeev","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090207591285800_cit45","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1021\/acs.jmedchem.6b01767","article-title":"Room Temperature Neutron Crystallography of Drug Resistant\nHIV-1 Protease Uncovers Limitations of X-ray Structure Analysis at\n100K","volume":"60","author":"Gerlits","year":"2017","journal-title":"J. Med. Chem."},{"key":"2026090207591285800_cit46","doi-asserted-by":"publisher","first-page":"4924","DOI":"10.1002\/anie.201509989","article-title":"Long-Range Electrostatics-Induced Two-Proton Transfer\nCaptured by Neutron Crystallography in an Enzyme Catalytic Site","volume":"55","author":"Gerlits","year":"2016","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090207591285800_cit47","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1002\/1521-3773(20020104)41:1&lt;48::aid-anie48&gt;3.0.co;2-u","article-title":"The hydrogen\nbond in the solid state","volume":"41","author":"Steiner","year":"2002","journal-title":"Angew. Chem., Int.\nEd."},{"key":"2026090207591285800_cit48","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1021\/acscatal.8b04142","article-title":"An n\u2192\u03c0*\nInteraction in the Bound Substrate of Aspartic Proteases Replicates\nthe Oxyanion Hole","volume":"9","author":"Windsor","year":"2019","journal-title":"ACS Catal."},{"key":"2026090207591285800_cit49","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1016\/s0968-0896(00)82041-6","article-title":"HIV-1 Protease Inhibitors: Ketomethylene Isosteres\nwith Unusually High Affinity Compared with Hydroxyethylene Isostere\nAnalogs","volume":"2","author":"Marinier","year":"1994","journal-title":"Bioorg. Med. Chem."},{"key":"2026090207591285800_cit50","doi-asserted-by":"publisher","first-page":"13459","DOI":"10.1074\/jbc.m708506200","article-title":"Effect of the Active Site D25N Mutation on the Structure,\nStability, and Ligand Binding of the Mature HIV-1 Protease","volume":"283","author":"Sayer","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2026090207591285800_cit51","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1038\/12327","article-title":"Autoprocessing of HIV-1 Protease\nis Tightly Coupled to Protein Folding","volume":"6","author":"Louis","year":"1999","journal-title":"Nat.\nStruct. Biol."},{"key":"2026090207591285800_cit52","doi-asserted-by":"publisher","first-page":"12957","DOI":"10.1021\/bi960984y","article-title":"Influence of Flanking\nSequences on the Dimer Stability of Human Immunodeficiency Virus Type\n1 Protease","volume":"35","author":"Wondrak","year":"1996","journal-title":"Biochemistry"},{"key":"2026090207591285800_cit53","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/prot.1057","article-title":"Structural\nImplications of Drug-Resistant Mutants of HIV-1 Protease: High-Resolution\nCrystal Structures of the Mutant Protease\/Substrate Analogue Complexes","volume":"43","author":"Mahalingam","year":"2001","journal-title":"Proteins: Struct., Funct., Genet."},{"key":"2026090207591285800_cit54","doi-asserted-by":"publisher","first-page":"9072","DOI":"10.1073\/pnas.1102278108","article-title":"Inhibition of Autoprocessing\nof Natural Variants and Multidrug Resistant Mutant Precursors of HIV-1\nProtease by Clinical Inhibitors","volume":"108","author":"Louis","year":"2011","journal-title":"Proc. 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