{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T04:44:53Z","timestamp":1789793093786,"version":"4.0.1"},"reference-count":100,"publisher":"AIP Publishing","issue":"21","funder":[{"name":"CEA-Riken Collaboration"},{"name":"MaX EU Center of Excellence","award":["EU-824143"],"award-info":[{"award-number":["EU-824143"]}]},{"name":"French LabeX CaPPA","award":["ANR-11-LABX-0005-01"],"award-info":[{"award-number":["ANR-11-LABX-0005-01"]}]},{"name":"ANR Project OVERSEE","award":["ANR-16-IDEX-0004"],"award-info":[{"award-number":["ANR-16-IDEX-0004"]}]},{"name":"CPER CLIMIBIO"}],"content-domain":{"domain":["pubs.aip.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,6,7]]},"abstract":"<jats:p>We present a hybrid, multi-method, computational scheme for protein\/ligand systems well suited to be used on modern and forthcoming massively parallel computing systems. The scheme relies on a multi-scale polarizable molecular modeling, approach to perform molecular dynamics simulations, and on an efficient Density Functional Theory (DFT) linear scaling method to post-process simulation snapshots. We use this scheme to investigate recent \u03b1-ketoamide inhibitors targeting the main protease of the SARS-CoV-2 virus. We assessed the reliability and the coherence of the hybrid scheme, in particular, by checking the ability of MM and DFT to reproduce results from high-end ab\u00a0initio computations regarding such inhibitors. The DFT approach enables an a posteriori fragmentation of the system and an investigation into the strength of interaction among identified fragment pairs. We show the necessity of accounting for a large set of plausible protease\/inhibitor conformations to generate reliable interaction data. Finally, we point out ways to further improve \u03b1-ketoamide inhibitors to more strongly interact with particular protease domains neighboring the active site.<\/jats:p>","DOI":"10.1063\/5.0148064","type":"journal-article","created":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T06:28:10Z","timestamp":1685946490000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Protein\u2013ligand interactions from a quantum fragmentation perspective: The case of the SARS-CoV-2 main protease interacting with\n                    <i>\u03b1<\/i>\n                    -ketoamide inhibitors"],"prefix":"10.1063","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1747-0247","authenticated-orcid":false,"given":"Luigi","family":"Genovese","sequence":"first","affiliation":[{"name":"Univ. Grenoble Alpes, CEA, IRIG-MEM-L_Sim 1 , 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4480-8565","authenticated-orcid":false,"given":"William","family":"Dawson","sequence":"additional","affiliation":[{"name":"RIKEN Center for Computational Science 2 , Kobe, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0229-3666","authenticated-orcid":false,"given":"Takahito","family":"Nakajima","sequence":"additional","affiliation":[{"name":"RIKEN Center for Computational Science 2 , Kobe, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3608-9222","authenticated-orcid":false,"given":"Viviana","family":"Cristiglio","sequence":"additional","affiliation":[{"name":"Institut Laue Langevin 3 , 71 Av. des Martyrs, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2202-3858","authenticated-orcid":false,"given":"Val\u00e9rie","family":"Vallet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille, CNRS, UMR 8523 - PhLAM - Physique des Lasers Atomes et Mol\u00e9cules 4 , F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1073-4457","authenticated-orcid":false,"given":"Michel","family":"Masella","sequence":"additional","affiliation":[{"name":"Laboratoire de Biologie Structurale et Radiobiologie, Service de Bio\u00e9nerg\u00e9tique, Biologie Structurale et M\u00e9canismes, Institut Joliot, CEA Saclay 5 , F-91191 Gif sur Yvette Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2023,6,5]]},"reference":[{"key":"2023081121392865300_c1","doi-asserted-by":"publisher","first-page":"e1574","DOI":"10.1002\/wcms.1574","article-title":"Density functional theory calculations of large systems: Interplay between fragments, observables, and computational complexity","volume":"12","year":"2022","journal-title":"Wiley Interdiscip. Rev.: Comput. Mol. Sci."},{"key":"2023081121392865300_c2","doi-asserted-by":"publisher","first-page":"e1290","DOI":"10.1002\/wcms.1290","article-title":"Challenges in large scale quantum mechanical calculations","volume":"7","year":"2017","journal-title":"Wiley Interdiscip. Rev.: Comput. Mol. Sci."},{"key":"2023081121392865300_c3","doi-asserted-by":"publisher","first-page":"10626","DOI":"10.1039\/D0SC02823A","article-title":"Revealing the molecular mechanisms of proteolysis of SARS-CoV-2 Mpro by QM\/MM computational methods","volume":"11","year":"2020","journal-title":"Chem. Sci."},{"key":"2023081121392865300_c4","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1039\/D0SC06195F","article-title":"Mechanism of inhibition of SARS-CoV-2 Mpro by N3 peptidyl Michael acceptor explained by QM\/MM simulations and design of new derivatives with tunable chemical reactivity","volume":"12","year":"2021","journal-title":"Chem. Sci."},{"key":"2023081121392865300_c5","doi-asserted-by":"publisher","first-page":"6746","DOI":"10.1039\/d1cp00266j","article-title":"Covalent and non-covalent binding free energy calculations for peptidomimetic inhibitors of SARS-CoV-2 main protease","volume":"23","year":"2021","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2023081121392865300_c6","doi-asserted-by":"publisher","first-page":"4157","DOI":"10.1021\/acscatal.0c05522","article-title":"Multiscale simulations of SARS-CoV-2 3CL protease inhibition with aldehyde derivatives. Role of protein and inhibitor conformational changes in the reaction mechanism","volume":"11","year":"2021","journal-title":"ACS Catal."},{"key":"2023081121392865300_c7","doi-asserted-by":"publisher","first-page":"3489","DOI":"10.1039\/D0SC04978F","article-title":"A microscopic description of SARS-CoV-2 main protease inhibition with Michael acceptors. Strategies for improving inhibitor design","volume":"12","year":"2021","journal-title":"Chem. Sci."},{"key":"2023081121392865300_c8","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1007\/s11030-021-10259-7","article-title":"New insights into the catalytic mechanism of the SARS-CoV-2 main protease: An ONIOM QM\/MM approach","volume":"26","year":"2022","journal-title":"Mol. Diversity"},{"key":"2023081121392865300_c9","doi-asserted-by":"publisher","first-page":"185101","DOI":"10.1063\/5.0123698","article-title":"Polarizable MD and QM\/MM investigation of acrylamide-based leads to target the main protease of SARS-CoV-2","volume":"157","year":"2022","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c10","doi-asserted-by":"publisher","first-page":"11287","DOI":"10.1021\/acs.chemrev.1c00965","article-title":"Methodology-centered review of molecular modeling, simulation, and prediction of SARS-CoV-2","volume":"122","year":"2022","journal-title":"Chem. Rev."},{"key":"2023081121392865300_c11","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1021\/acscatal.1c04661","article-title":"Impact of warhead modulations on the covalent inhibition of SARS-CoV-2 Mpro explored by QM\/MM simulations","volume":"12","year":"2022","journal-title":"ACS Catal."},{"key":"2023081121392865300_c12","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1016\/j.drudis.2021.12.017","article-title":"Applications of density functional theory in COVID-19 drug modeling","volume":"27","year":"2022","journal-title":"Drug Discovery Today"},{"key":"2023081121392865300_c13","doi-asserted-by":"publisher","first-page":"e202203319","DOI":"10.1002\/slct.202203319","article-title":"QM\/MM studies on enzyme catalysis and insight into designing of new inhibitors by ONIOM approach: Recent update","volume":"8","year":"2023","journal-title":"ChemistrySelect"},{"key":"2023081121392865300_c14","doi-asserted-by":"publisher","first-page":"5056","DOI":"10.1021\/acs.jctc.2c00286","article-title":"How reproducible are QM\/MM simulations? Lessons from computational studies of the covalent inhibition of the SARS-CoV-2 main protease by carmofur","volume":"18","year":"2022","journal-title":"J. Chem. Theory Comput."},{"key":"2023081121392865300_c15","doi-asserted-by":"publisher","first-page":"4079","DOI":"10.1021\/acs.jctc.7b00291","article-title":"Complexity reduction in large quantum systems: Fragment identification and population analysis via a local optimized minimal basis","volume":"13","year":"2017","journal-title":"J. Chem. Theory Comput."},{"key":"2023081121392865300_c16","doi-asserted-by":"publisher","first-page":"2952","DOI":"10.1021\/acs.jctc.9b01152","article-title":"Complexity reduction in density functional theory calculations of large systems: System partitioning and fragment embedding","volume":"16","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"2023081121392865300_c17","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1002\/jcc.20496","article-title":"Pair interaction energy decomposition analysis","volume":"28","year":"2007","journal-title":"J. Comput. Chem."},{"key":"2023081121392865300_c18","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1021\/acs.jctc.6b01230","article-title":"Intuitive density functional theory-based energy decomposition analysis for protein\u2013ligand interactions","volume":"13","year":"2017","journal-title":"J. Chem. Theory Comput."},{"key":"2023081121392865300_c19","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.copbio.2019.09.006","article-title":"Designing a bioremediator: Mechanistic models guide cellular and molecular specialization","volume":"62","year":"2020","journal-title":"Curr. Opin. Biotechnol."},{"key":"2023081121392865300_c20","doi-asserted-by":"publisher","first-page":"3758","DOI":"10.1021\/acs.jcim.1c00404","article-title":"Strengths and weaknesses of docking simulations in the SARS-CoV-2 era: The main protease (Mpro) case study","volume":"61","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"2023081121392865300_c21","doi-asserted-by":"publisher","first-page":"9121","DOI":"10.1039\/D0CS01065K","article-title":"A critical overview of computational approaches employed for COVID-19 drug discovery","volume":"50","year":"2021","journal-title":"Chem. Soc. Rev."},{"key":"2023081121392865300_c22","doi-asserted-by":"publisher","first-page":"3593","DOI":"10.1021\/acs.jcim.0c00283","article-title":"Fragment molecular orbital based interaction analyses on COVID-19 main protease - inhibitor N3 complex (PDB ID: 6LU7)","volume":"60","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"2023081121392865300_c23","doi-asserted-by":"publisher","first-page":"106510","DOI":"10.1016\/j.bpc.2020.106510","article-title":"An insight into the interaction between \u03b1-ketoamide-based inhibitor and coronavirus main protease: A detailed in silico study","volume":"269","year":"2021","journal-title":"Biophys. Chem."},{"key":"2023081121392865300_c24","doi-asserted-by":"publisher","first-page":"4594","DOI":"10.1021\/acs.jcim.1c00694","article-title":"Special features of COVID-19 in the FMODB: Fragment molecular orbital calculations and interaction energy analysis of SARS-CoV-2-related proteins","volume":"61","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"2023081121392865300_c25","doi-asserted-by":"publisher","first-page":"11267","DOI":"10.1021\/acs.jpclett.1c02788","article-title":"Interaction analysis on the SARS-CoV-2 spike protein receptor binding domain using visualization of the interfacial electrostatic complementarity","volume":"12","year":"2021","journal-title":"J. Chem. Phys. Lett."},{"key":"2023081121392865300_c26","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1021\/acs.jcim.2c00100","article-title":"Interaction analysis of the spike protein of delta and omicron variants of SARS-CoV-2 with hACE2 and eight monoclonal antibodies using the fragment molecular orbital method","volume":"62","year":"2022","journal-title":"J. Chem. Inf. Model."},{"key":"2023081121392865300_c27","doi-asserted-by":"publisher","first-page":"4059","DOI":"10.1021\/acs.jpclett.1c00663","article-title":"Intermolecular interaction analyses on SARS-CoV-2 spike protein receptor binding domain and human angiotensin-converting enzyme 2 receptor-blocking antibody\/peptide using fragment molecular orbital calculation","volume":"12","year":"2021","journal-title":"J. Chem. Phys. Lett."},{"key":"2023081121392865300_c28","doi-asserted-by":"publisher","first-page":"4722","DOI":"10.1039\/D0SC06528E","article-title":"Molecular recognition of SARS-CoV-2 spike glycoprotein: Quantum chemical hot spot and epitope analyses","volume":"12","year":"2021","journal-title":"Chem. Sci."},{"key":"2023081121392865300_c29","doi-asserted-by":"publisher","first-page":"9478","DOI":"10.1021\/jp404518r","article-title":"Free energies of binding from large-scale first-principles quantum mechanical calculations: Application to ligand hydration energies","volume":"117","year":"2013","journal-title":"J. Phys. Chem. B"},{"key":"2023081121392865300_c30","doi-asserted-by":"publisher","first-page":"137883","DOI":"10.1016\/j.cplett.2020.137883","article-title":"Machine learning prediction of inter-fragment interaction energies between ligand and amino-acid residues on the fragment molecular orbital calculations for Janus kinase \u2013 inhibitor complex","volume":"757","year":"2020","journal-title":"Chem. Phys. Lett."},{"key":"2023081121392865300_c31","doi-asserted-by":"publisher","first-page":"6501","DOI":"10.1021\/acs.jpcb.1c03043","article-title":"Dynamic cooperativity of ligand\u2013residue interactions evaluated with the fragment molecular orbital method","volume":"125","year":"2021","journal-title":"J. Phys. Chem. B"},{"key":"2023081121392865300_c32","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1002\/jcc.26940","article-title":"Protein-ligand binding affinity prediction of cyclin-dependent kinase-2 inhibitors by dynamically averaged fragment molecular orbital-based interaction energy","volume":"43","year":"2022","journal-title":"J. Comput. Chem."},{"key":"2023081121392865300_c33","doi-asserted-by":"publisher","first-page":"4413","DOI":"10.1021\/acs.jpclett.0c00994","article-title":"In silico exploration of the molecular mechanism of clinically oriented drugs for possibly inhibiting SARS-CoV-2\u2019s main protease","volume":"11","year":"2020","journal-title":"J. Phys. Chem. Lett."},{"key":"2023081121392865300_c34","doi-asserted-by":"publisher","first-page":"2607","DOI":"10.1080\/07391102.2020.1751298","article-title":"Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach","volume":"39","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"2023081121392865300_c35","doi-asserted-by":"publisher","first-page":"225","DOI":"10.3390\/md18040225","article-title":"Putative inhibitors of SARS-CoV-2 main protease from a library of marine natural products: A virtual screening and molecular modeling study","volume":"18","year":"2020","journal-title":"Mar. Drugs"},{"key":"2023081121392865300_c36","doi-asserted-by":"publisher","first-page":"5754","DOI":"10.1021\/acs.jcim.0c00326","article-title":"Discovery of new hydroxyethylamine analogs against 3CLpro protein target of SARS-CoV-2: Molecular docking, molecular dynamics simulation, and structure-activity relationship studies","volume":"60","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"2023081121392865300_c37","author":"D. E. Shaw Research","year":"2020"},{"key":"2023081121392865300_c38","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1021\/acs.jctc.7b00067","article-title":"Polarizable force field for DNA based on the classical Drude oscillator: I. Refinement using quantum mechanical base stacking and conformational energetics","volume":"13","year":"2017","journal-title":"J. Chem. Theory Comput."},{"key":"2023081121392865300_c39","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.sbi.2019.12.012","article-title":"Polarisable force fields: What do they add in biomolecular simulations?","volume":"61","year":"2020","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2023081121392865300_c40","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1021\/acs.jpcb.9b09553","article-title":"Driving force for the complexation of charged polypeptides","volume":"124","year":"2020","journal-title":"J. Phys. Chem. B"},{"key":"2023081121392865300_c41","doi-asserted-by":"publisher","first-page":"114903","DOI":"10.1063\/5.0056508","article-title":"Hybrid polarizable simulations of a conventional hydrophobic polyelectrolyte. Toward a theoretical tool for green science innovation","volume":"155","year":"2021","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c42","doi-asserted-by":"publisher","first-page":"1866","DOI":"10.1063\/1.1579478","article-title":"A many-body model to study proteins. I. Applications to MLnm+ complexes, Mm+ = Li+, Na+, K+, Mg2+, Ca2+, and Zn2+, L = H2O, CH3OH, HCONH2, n = 1\u20136, and to small hydrogen bonded systems","volume":"119","year":"2003","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c43","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1002\/jcc.20932","article-title":"Combining a polarizable force-field and a coarse-grained polarizable solvent model: Application to long dynamics simulations of bovine pancreatic trypsin inhibitor","volume":"29","year":"2008","journal-title":"J. Comput. Chem."},{"key":"2023081121392865300_c44","doi-asserted-by":"publisher","first-page":"2664","DOI":"10.1002\/jcc.21846","article-title":"Combining a polarizable force-field and a coarse-grained polarizable solvent model. II. Accounting for hydrophobic effects","volume":"32","year":"2011","journal-title":"J. Comput. Chem."},{"key":"2023081121392865300_c45","doi-asserted-by":"publisher","first-page":"194110","DOI":"10.1063\/5.0004792","article-title":"Flexibilities of wavelets as a computational basis set for large-scale electronic structure calculations","volume":"152","year":"2020","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c46","doi-asserted-by":"publisher","first-page":"014109","DOI":"10.1063\/1.2949547","article-title":"Daubechies wavelets as a basis set for density functional pseudopotential calculations","volume":"129","year":"2008","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c47","doi-asserted-by":"publisher","first-page":"3508","DOI":"10.1021\/acs.jmedchem.0c01808","article-title":"The alpha keto amide moiety as a privileged motif in medicinal chemistry: Current insights and emerging opportunities","volume":"64","year":"2021","journal-title":"J. Med. Chem."},{"key":"2023081121392865300_c48","doi-asserted-by":"publisher","first-page":"4562","DOI":"10.1021\/acs.jmedchem.9b01828","article-title":"\u03b1-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication: Structure-based design, synthesis, and activity assessment","volume":"63","year":"2020","journal-title":"J. Med. Chem."},{"key":"2023081121392865300_c49","doi-asserted-by":"publisher","first-page":"6595","DOI":"10.1021\/acs.jmedchem.5b01461","article-title":"An overview of severe acute respiratory syndrome\u2013coronavirus (SARS-CoV) 3CL protease inhibitors: Peptidomimetics and small molecule chemotherapy","volume":"59","year":"2016","journal-title":"J. Med. Chem."},{"key":"2023081121392865300_c50","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1016\/j.chembiol.2017.09.007","article-title":"General and modular strategy for designing potent, selective, and pharmacologically compliant inhibitors of rhomboid proteases","volume":"24","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"2023081121392865300_c51","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1126\/science.abb3405","article-title":"Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved \u03b1-ketoamide inhibitors","volume":"368","year":"2020","journal-title":"Science"},{"key":"2023081121392865300_c52","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors","volume":"582","year":"2020","journal-title":"Nature"},{"key":"2023081121392865300_c53","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/s41594-020-0440-6","article-title":"Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur","volume":"27","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2023081121392865300_c54","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1126\/science.abb4489","article-title":"Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease","volume":"368","year":"2020","journal-title":"Science"},{"key":"2023081121392865300_c55","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.4155\/fmc-2020-0180","article-title":"Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics","volume":"12","year":"2020","journal-title":"Future Med. Chem."},{"key":"2023081121392865300_c56","doi-asserted-by":"publisher","article-title":"Structure of human coronavirus NL63 main protease in complex with the alpha-ketoamide tert-butyl ((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)b- utan-2-yl)carbamate (tert-butyl -GlnLactam-CO-CO-NH-benzyl)","year":"2018","DOI":"10.2210\/pdb5NH0\/pdb"},{"key":"2023081121392865300_c57","doi-asserted-by":"publisher","first-page":"161720","DOI":"10.1063\/1.4997996","article-title":"Organic ion association in aqueous phase and ab\u00a0initio-based force fields: The case of carboxylate\/ammonium salts","volume":"147","year":"2017","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c58","doi-asserted-by":"publisher","first-page":"4721","DOI":"10.1021\/bi00181a032","article-title":"Two crystal structures of the B1 immunoglobulin-binding domain of streptococcal protein G and comparison with NMR","volume":"33","year":"1994","journal-title":"Biochemistry"},{"key":"2023081121392865300_c59","doi-asserted-by":"publisher","first-page":"13686","DOI":"10.1039\/D1SC03628A","article-title":"Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding","volume":"12","year":"2021","journal-title":"Chem. Sci."},{"key":"2023081121392865300_c60","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","year":"2015","journal-title":"SoftwareX"},{"key":"2023081121392865300_c61","doi-asserted-by":"publisher","first-page":"1950","DOI":"10.1002\/prot.22711","article-title":"Improved side-chain torsion potentials for the amber ff99SB protein force field","volume":"78","year":"2010","journal-title":"Proteins"},{"key":"2023081121392865300_c62","unstructured":"See http:\/\/biodev.cea.fr\/polaris\/ for information about the POLARIS code."},{"key":"2023081121392865300_c63","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1080\/00268970500404414","article-title":"The multiple time step r-RESPA procedure and polarizable potentials based on induced dipole moments","volume":"104","year":"2006","journal-title":"Mol. Phys."},{"key":"2023081121392865300_c64","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1051\/m2an:2007014","article-title":"Theoretical and numerical comparison of some sampling methods for molecular dynamics","volume":"41","year":"2007","journal-title":"ESAIM: M2AN"},{"key":"2023081121392865300_c65","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1080\/00268979600100761","article-title":"Explicit reversible integrators for extended systems dynamics","volume":"87","year":"1996","journal-title":"Mol. Phys."},{"key":"2023081121392865300_c66","doi-asserted-by":"publisher","first-page":"3213","DOI":"10.1093\/emboj\/cdf327","article-title":"Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra \u03b1-helical domain","volume":"21","year":"2002","journal-title":"EMBO J."},{"key":"2023081121392865300_c67","doi-asserted-by":"publisher","first-page":"5815","DOI":"10.1021\/acs.jcim.0c00575","article-title":"SARS-CoV-2 main protease: A molecular dynamics study","volume":"60","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"2023081121392865300_c68","doi-asserted-by":"publisher","first-page":"3099","DOI":"10.3390\/ijms21093099","article-title":"Structural and evolutionary analysis indicate that the SARS-CoV-2 Mpro is a challenging target for small-molecule inhibitor design","volume":"21","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"2023081121392865300_c69","unstructured":"See http:\/\/www.bigdft.org for information about the BigDFT code."},{"key":"2023081121392865300_c70","doi-asserted-by":"publisher","first-page":"3865","DOI":"10.1103\/PhysRevLett.77.3865","article-title":"Generalized gradient approximation made simple","volume":"77","year":"1996","journal-title":"Phys. Rev. Lett."},{"key":"2023081121392865300_c71","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1002\/jcc.21759","article-title":"Effect of the damping function in dispersion corrected density functional theory","volume":"32","year":"2011","journal-title":"J. Comput. Chem."},{"key":"2023081121392865300_c72","doi-asserted-by":"publisher","first-page":"104109","DOI":"10.1063\/1.4793260","article-title":"Norm-conserving pseudopotentials with chemical accuracy compared to all-electron calculations","volume":"138","year":"2013","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c73","doi-asserted-by":"publisher","first-page":"084119","DOI":"10.1063\/1.1839852","article-title":"Introducing ONETEP: Linear-scaling density functional simulations on parallel computers","volume":"122","year":"2005","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c74","doi-asserted-by":"publisher","first-page":"074207","DOI":"10.1088\/0953-8984\/22\/7\/074207","article-title":"Calculations for millions of atoms with density functional theory: Linear scaling shows its potential","volume":"22","year":"2010","journal-title":"J. Phys.: Condens. Matter"},{"key":"2023081121392865300_c75","doi-asserted-by":"publisher","first-page":"pgac180","DOI":"10.1093\/pnasnexus\/pgac180","article-title":"Probing the mutational landscape of the SARS-CoV-2 spike protein via quantum mechanical modeling of crystallographic structures","volume":"1","year":"2022","journal-title":"PNAS Nexus"},{"key":"2023081121392865300_c76","volume-title":"Gaussian 09, Revision D.01","year":"2009"},{"key":"2023081121392865300_c77","doi-asserted-by":"publisher","first-page":"3650","DOI":"10.1021\/acs.jctc.7b00554","article-title":"Scalable electron correlation methods. 3. Efficient and accurate parallel local coupled cluster with pair natural orbitals (PNO-LCCSD)","volume":"13","year":"2017","journal-title":"J. Chem. Theory Comput."},{"key":"2023081121392865300_c78","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1021\/acs.jctc.7b01141","article-title":"Scalable electron correlation methods. 5. Parallel perturbative triples correction for explicitly correlated local coupled cluster with pair natural orbitals","volume":"14","year":"2018","journal-title":"J. Chem. Theory Comput."},{"key":"2023081121392865300_c79","volume-title":"molpro, version 2019.2, a package of ab\u00a0initio programs","year":"2019"},{"key":"2023081121392865300_c80","doi-asserted-by":"publisher","first-page":"6796","DOI":"10.1063\/1.462569","article-title":"Electron affinities of the first-row atoms revisited. Systematic basis sets and wave functions","volume":"96","year":"1992","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c81","doi-asserted-by":"publisher","first-page":"4285","DOI":"10.1039\/B204199P","article-title":"A fully direct RI-HF algorithm: Implementation, optimised auxiliary basis sets, demonstration of accuracy and efficiency","volume":"4","year":"2002","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2023081121392865300_c82","doi-asserted-by":"publisher","first-page":"3175","DOI":"10.1063\/1.1445115","article-title":"Efficient use of the correlation consistent basis sets in resolution of the identity MP2 calculations","volume":"116","year":"2002","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c83","doi-asserted-by":"publisher","article-title":"Crystal structure of the complex resulting from the reaction between the SARS-CoV main protease and tert-butyl (1-((S)-3-cyclohexyl-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate","year":"2020","DOI":"10.2210\/pdb6Y7M\/pdb"},{"key":"2023081121392865300_c84","doi-asserted-by":"publisher","article-title":"Crystal structure (orthorhombic form) of the complex resulting from the reaction between SARS-CoV-2 (2019-nCoV) main protease and tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (alpha-ketoamide 13b)","year":"2020","DOI":"10.2210\/pdb6Y2G\/pdb"},{"key":"2023081121392865300_c85","doi-asserted-by":"publisher","first-page":"4601","DOI":"10.1021\/acs.biochem.0c00782","article-title":"Exploring the mechanism of covalent inhibition: Simulating the binding free energy of \u03b1-ketoamide inhibitors of the main protease of SARS-CoV-2","volume":"59","year":"2020","journal-title":"Biochemistry"},{"key":"2023081121392865300_c86","doi-asserted-by":"publisher","first-page":"17365","DOI":"10.1074\/jbc.AC120.016154","article-title":"Unusual zwitterionic catalytic site of SARS-CoV-2 main protease revealed by neutron crystallography","volume":"295","year":"2020","journal-title":"J. Mol. Bio."},{"key":"2023081121392865300_c87","doi-asserted-by":"publisher","first-page":"139489","DOI":"10.1016\/j.cplett.2022.139489","article-title":"Multiple protonation states in ligand-free SARS-CoV-2 main protease revealed by large-scale quantum molecular dynamics simulations","volume":"794","year":"2022","journal-title":"Chem. Phys. Lett."},{"key":"2023081121392865300_c88","doi-asserted-by":"publisher","first-page":"17366","DOI":"10.1021\/acs.jmedchem.1c01475","article-title":"Structural, electronic, and electrostatic determinants for inhibitor binding to subsites S1 and S2 in SARS-CoV-2 main protease","volume":"64","year":"2021","journal-title":"J. Med. Chem."},{"key":"2023081121392865300_c89","doi-asserted-by":"publisher","first-page":"4991","DOI":"10.1021\/acs.jmedchem.1c00058","article-title":"Direct observation of protonation state modulation in SARS-CoV-2 main protease upon inhibitor binding with neutron crystallography","volume":"64","year":"2021","journal-title":"J. Med. Chem."},{"key":"2023081121392865300_c90","doi-asserted-by":"publisher","first-page":"2427","DOI":"10.1021\/ct2002946","article-title":"S66: A well-balanced database of benchmark interaction energies relevant to biomolecular structures","volume":"7","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"2023081121392865300_c91","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1107\/S090744490903145X","article-title":"Protein flexibility: Coordinate uncertainties and interpretation of structural differences","volume":"65","year":"2009","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"key":"2023081121392865300_c92","doi-asserted-by":"publisher","first-page":"114594","DOI":"10.1016\/j.ab.2022.114594","article-title":"The reproducible normality of the crystallographic B-factor","volume":"645","year":"2022","journal-title":"Anal. Biochem."},{"key":"2023081121392865300_c93","doi-asserted-by":"publisher","first-page":"23099","DOI":"10.1039\/D0CP04326E","article-title":"Discovery of potent inhibitors for SARS-CoV-2\u2019s main protease by ligand-based\/structure-based virtual screening, MD simulations, and binding energy calculations","volume":"22","year":"2020","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2023081121392865300_c94","doi-asserted-by":"publisher","first-page":"5314","DOI":"10.1039\/D1CC01449H","article-title":"Influence of charge configuration on substrate binding to SARS-CoV-2 main protease","volume":"57","year":"2021","journal-title":"Chem. Commun."},{"key":"2023081121392865300_c95","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1039\/D0SC04942E","article-title":"Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease","volume":"12","year":"2021","journal-title":"Chem. Sci."},{"key":"2023081121392865300_c96","doi-asserted-by":"publisher","first-page":"4195","DOI":"10.1021\/acs.jpclett.1c00425","article-title":"Tuning proton transfer thermodynamics in SARS-CoV-2 main protease: Implications for catalysis and inhibitor design","volume":"12","year":"2021","journal-title":"J. Chem. Phys. Lett."},{"key":"2023081121392865300_c97","doi-asserted-by":"publisher","first-page":"5687","DOI":"10.1063\/1.449928","article-title":"Natural bond orbital analysis of molecular interactions: Theoretical studies of binary complexes of HF, H2O, NH3, N2, O2, F2, CO, and CO2 with HF, H2O, and NH3","volume":"84","year":"1986","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c98","doi-asserted-by":"publisher","first-page":"124508","DOI":"10.1063\/1.3478999","article-title":"Structural and atoms-in-molecules analysis of hydrogen-bond network around nitroxides in liquid water","volume":"133","year":"2010","journal-title":"J. Chem. Phys."},{"key":"2023081121392865300_c99","doi-asserted-by":"publisher","first-page":"29940","DOI":"10.1039\/d2cp03681a","article-title":"Optimization of potential non-covalent inhibitors for the SARS-CoV-2 main protease inspected by a descriptor of the subpocket occupancy","volume":"24","year":"2022","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2023081121392865300_c100","doi-asserted-by":"publisher","first-page":"4669","DOI":"10.1016\/j.csbj.2021.08.015","article-title":"Non-conventional interactions of N3 inhibitor with the main protease of SARS-CoV and SARS-CoV-2","volume":"19","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."}],"container-title":["The Journal of Chemical Physics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.aip.org\/aip\/jcp\/article-pdf\/doi\/10.1063\/5.0148064\/17943572\/214121_1_5.0148064.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.aip.org\/aip\/jcp\/article-pdf\/doi\/10.1063\/5.0148064\/17943572\/214121_1_5.0148064.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T17:39:49Z","timestamp":1691775589000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.aip.org\/jcp\/article\/158\/21\/214121\/2894430\/Protein-ligand-interactions-from-a-quantum"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,5]]},"references-count":100,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2023,6,7]]}},"URL":"https:\/\/doi.org\/10.1063\/5.0148064","relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv.12924974.v2","asserted-by":"object"}]},"ISSN":["0021-9606","1089-7690"],"issn-type":[{"value":"0021-9606","type":"print"},{"value":"1089-7690","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,6,7]]},"published":{"date-parts":[[2023,6,5]]},"article-number":"214121"}}