{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:29:57Z","timestamp":1772252997891,"version":"3.50.1"},"reference-count":89,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T00:00:00Z","timestamp":1645660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The SARS-CoV-2 Delta variant is emerging as a globally dominant strain. Its rapid spread and high infection rate are attributed to a mutation in the spike protein of SARS-CoV-2 allowing for the virus to invade human cells much faster and with an increased efficiency. In particular, an especially dangerous mutation P681R close to the furin cleavage site has been identified as responsible for increasing the infection rate. Together with the earlier reported mutation D614G in the same domain, it offers an excellent instance to investigate the nature of mutations and how they affect the interatomic interactions in the spike protein. Here, using ultra large-scale ab initio computational modeling, we study the P681R and D614G mutations in the SD2-FP domain, including the effect of double mutation, and compare the results with the wild type. We have recently developed a method of calculating the amino-acid\u2013amino-acid bond pairs (AABP) to quantitatively characterize the details of the interatomic interactions, enabling us to explain the nature of mutation at the atomic resolution. Our most significant finding is that the mutations reduce the AABP value, implying a reduced bonding cohesion between interacting residues and increasing the flexibility of these amino acids to cause the damage. The possibility of using this unique mutation quantifiers in a machine learning protocol could lead to the prediction of emerging mutations.<\/jats:p>","DOI":"10.3390\/v14030465","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T21:11:52Z","timestamp":1645737112000},"page":"465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Delta Variant with P681R Critical Mutation Revealed by Ultra-Large Atomic-Scale Ab Initio Simulation: Implications for the Fundamentals of Biomolecular Interactions"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5591-6505","authenticated-orcid":false,"given":"Puja","family":"Adhikari","sequence":"first","affiliation":[{"name":"Department of Physics and Astronomy, University of Missouri-Kansas City, Kansas City, MO 64110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6252-3999","authenticated-orcid":false,"given":"Bahaa","family":"Jawad","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, University of Missouri-Kansas City, Kansas City, MO 64110, USA"},{"name":"Department of Applied Sciences, University of Technology, Baghdad 10066, Iraq"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Praveen","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Health Management and Informatics, Department of Electrical Engineering and Computer Science, University of Missouri-Columbia, Columbia, MO 65212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3855-4637","authenticated-orcid":false,"given":"Rudolf","family":"Podgornik","sequence":"additional","affiliation":[{"name":"School of Physical Sciences and Kavli Institute of Theoretical Science, University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"CAS Key Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100090, China"},{"name":"Wenzhou Institute of the University of Chinese Academy of Sciences, Wenzhou 325000, China"},{"name":"Department of Physics, Faculty of Mathematics and Physics, University of Ljubljana, SI-1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7738-8822","authenticated-orcid":false,"given":"Wai-Yim","family":"Ching","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, University of Missouri-Kansas City, Kansas City, MO 64110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1016\/S0140-6736(03)14630-2","article-title":"Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People\u2019s Republic of China, in February, 2003","volume":"362","author":"Zhong","year":"2003","journal-title":"Lancet"},{"key":"ref_2","unstructured":"Rambaut, A., Loman, N., Pybus, O., Barclay, W., Barrett, J., Carabelli, A., Connor, T., Peacock, T., Robertson, D.L., and Volz, E. (2021, September 22). Preliminary Genomic Haracterization of an Emergent SARS-CoV-2 Lineage in the UK Defined by a Novel Set of Spike Mutations. SARS-CoV-2 Coronavirus nCoV-2019 Genomic Epidemiology. Virological 2020. Available online: https:\/\/virological.org\/t\/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations\/563."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Tegally, H., Wilkinson, E., Giovanetti, M., Iranzadeh, A., Fonseca, V., Giandhari, J., Doolabh, D., Pillay, S., San, E.J., and Msomi, N. (2020). Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. MedRxiv.","DOI":"10.1101\/2020.12.21.20248640"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/s41591-021-01397-4","article-title":"SARS-CoV-2 variants of concern are emerging in India","volume":"27","author":"Singh","year":"2021","journal-title":"Nat. Med."},{"key":"ref_5","first-page":"815","article-title":"Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: Preliminary findings","volume":"372","author":"Faria","year":"2021","journal-title":"Virological"},{"key":"ref_6","unstructured":"Ozer, E.A., Simons, L.M., Adewumi, O.M., Fowotade, A.A., Omoruyi, E.C., Adeniji, J.A., Dean, T.J., Taiwo, B.O., Hultquist, J.F., and Lorenzo-Redondo, R. (2021). High prevalence of SARS-CoV-2 B. 1.1. 7 (UK variant) and the novel B. 1.5. 2.5 lineage in Oyo State, Nigeria. MedRxiv."},{"key":"ref_7","unstructured":"Annavajhala, M.K., Mohri, H., Zucker, J.E., Sheng, Z., Wang, P., Gomez-Simmonds, A., Ho, D.D., and Uhlemann, A.-C. (2021). A novel SARS-CoV-2 variant of concern, B. 1.526, identified in New York. MedRxiv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4220.e13","DOI":"10.1016\/j.cell.2021.06.020","article-title":"Reduced neutralization of SARS-CoV-2 B. 1.617 by vaccine and convalescent serum","volume":"184","author":"Liu","year":"2021","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kimura, I., Kosugi, Y., Wu, J., Yamasoba, D., Butlertanaka, E.P., Tanaka, Y.L., Liu, Y., Shirakawa, K., Kazuma, Y., and Nomura, R. (2021). SARS-CoV-2 Lambda variant exhibits higher infectivity and immune resistance. BioRxiv.","DOI":"10.1101\/2021.07.28.454085"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Laiton-Donato, K., Franco-Munoz, C., Alvarez-Diaz, D.A., Ruiz-Moreno, H., Usme-Ciro, J., Prada, D., Reales, J., Corchuelo, S., Herrera-sepulveda, M., and Naizaque, J. (2021). Characterization of the emerging B. 1.621 variant of interest of SARS-CoV-2. MedRxiv.","DOI":"10.1101\/2021.05.08.21256619"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Reardon, S. (2021). How the Delta variant achieves its ultrafast spread. Nature, 21.","DOI":"10.1038\/d41586-021-01986-w"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"474","DOI":"10.7326\/M20-2223","article-title":"Historical Insights on Coronavirus Disease 2019 (COVID-19), the 1918 Influenza Pandemic, and Racial Disparities: Illuminating a Path Forward","volume":"173","author":"Krishnan","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_13","unstructured":"(2021, September 22). A Timeline of HIV and AIDS, Available online: https:\/\/www.hiv.gov\/hiv-basics\/overview\/history\/hiv-and-aids-timeline."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"20659","DOI":"10.2807\/1560-7917.ES2013.18.50.20659","article-title":"Middle East Respiratory Syndrome (MERS) coronavirus seroprevalence in domestic livestock in Saudi Arabia, 2010 to 2013","volume":"18","author":"Hemida","year":"2013","journal-title":"Eurosurveillance"},{"key":"ref_15","unstructured":"(2020, December 09). Preventing the Spread of the Coronavirus. Available online: https:\/\/www.health.harvard.edu\/diseases-and-conditions\/preventing-the-spread-of-the-coronavirus."},{"key":"ref_16","unstructured":"(2020, November 02). Understanding How COVID-19 Vaccines Work, Available online: https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/vaccines\/different-vaccines\/how-they-work.html."},{"key":"ref_17","unstructured":"(2021, November 01). COVID-19 Genomic Surveillance. Available online: https:\/\/covid19.sanger.ac.uk\/lineages\/raw."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1126\/science.abb2507","article-title":"Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation","volume":"367","author":"Wrapp","year":"2020","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/s41564-021-00908-w","article-title":"The furin cleavage site in the SARS-CoV-2 spike protein is required for transmission in ferrets","volume":"6","author":"Peacock","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"271.e8","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"104742","DOI":"10.1016\/j.antiviral.2020.104742","article-title":"The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade","volume":"176","author":"Coutard","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_23","first-page":"1","article-title":"The role of furin cleavage site in SARS-CoV-2 spike protein-mediated membrane fusion in the presence or absence of trypsin","volume":"5","author":"Xia","year":"2020","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101212","DOI":"10.1016\/j.isci.2020.101212","article-title":"Proteolytic cleavage of the SARS-CoV-2 spike protein and the role of the novel S1\/S2 site","volume":"23","author":"Jaimes","year":"2020","journal-title":"iScience"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Papa, G., Mallery, D.L., Albecka, A., Welch, L.G., Cattin-Ortol\u00e1, J., Luptak, J., Paul, D., McMahon, H.T., Goodfellow, I.G., and Carter, A. (2021). Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009246"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Liu, Y., Liu, J., Johnson, B.A., Xia, H., Ku, Z., Schindewolf, C., Widen, S.G., An, Z., Weaver, S.C., and Menachery, V.D. (2021). Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant. BioRxiv.","DOI":"10.1101\/2021.08.12.456173"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Peacock, T.P., Sheppard, C.M., Brown, J.C., Goonawardane, N., Zhou, J., Whiteley, M., de Silva, T.I., Barclay, W.S., and Consortium, P.V. (2021). The SARS-CoV-2 variants associated with infections in India, B. 1.617, show enhanced spike cleavage by furin. BioRxiv.","DOI":"10.1101\/2021.05.28.446163"},{"key":"ref_28","first-page":"17.448820","article-title":"SARS-CoV-2 spike P681R mutation enhances and accelerates viral fusion","volume":"10","author":"Saito","year":"2021","journal-title":"BioRxiv"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6013","DOI":"10.1038\/s41467-020-19808-4","article-title":"SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity","volume":"11","author":"Zhang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"108630","DOI":"10.1016\/j.celrep.2020.108630","article-title":"D614G mutation alters SARS-CoV-2 spike conformation and enhances protease cleavage at the S1\/S2 junction","volume":"34","author":"Gobeil","year":"2021","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"39831","DOI":"10.1039\/D0RA08222H","article-title":"Amino acid interacting network in the receptor-binding domain of SARS-CoV-2 spike protein","volume":"10","author":"Adhikari","year":"2020","journal-title":"RSC Adv."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7128","DOI":"10.1021\/acs.jpcb.0c04553","article-title":"Developing a fully glycosylated full-length SARS-CoV-2 spike protein model in a viral membrane","volume":"124","author":"Woo","year":"2020","journal-title":"J. Phys. Chem. B"},{"key":"ref_33","unstructured":"(2021, November 01). CHARMM-GUI Archive\u2014COVID-19 Proteins Library. Available online: https:\/\/charmm-gui.org\/?doc=archive&lib=covid19."},{"key":"ref_34","unstructured":"Case, D.A., Betz, R., Cerutti, D., Cheatham, T., Darden, T., Duke, R., Giese, T., Gohlke, H., Goetz, A., and Homeyer, N. (2021, November 01). AMBER 2020 Reference Manual. University of California, San Francisco, 2020. Available online: https:\/\/ambermd.org\/Manuals.php."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber biomolecular simulation programs","volume":"26","author":"Case","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0010-4655(95)00041-D","article-title":"AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules","volume":"91","author":"Pearlman","year":"1995","journal-title":"Comput. Phys. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/S0959-440X(02)00344-5","article-title":"Rotamer libraries in the 21st century","volume":"12","author":"Dunbrack","year":"2002","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_39","unstructured":"(2021, November 01). VASP\u2014Vienna Ab Initio Simulation Package. Available online: https:\/\/www.vasp.at\/."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ching, W.-Y., and Rulis, P. (2012). Electronic Structure Methods for Complex Materials: The Orthogonalized Linear Combination of Atomic Orbitals, Oxford University Press.","DOI":"10.1093\/acprof:oso\/9780199575800.001.0001"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"D1202","DOI":"10.1093\/nar\/gkv951","article-title":"PubChem substance and compound databases","volume":"44","author":"Kim","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ryadnov, M., and Hudecz, F. (2017). Amino Acids, Peptides and Proteins, Royal Society of Chemistry.","DOI":"10.1039\/9781788010627"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1080\/07391102.2020.1753577","article-title":"Targeting SARS-CoV-2: A systematic drug repurposing approach to identify promising inhibitors against 3C-like proteinase and 2\u2032-O-ribose methyltransferase","volume":"39","author":"Khan","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"13967","DOI":"10.1073\/pnas.2008209117","article-title":"Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions","volume":"117","author":"Wang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Marx, D., and Hutter, J. (2009). Ab Initio Molecular Dynamics: Basic Theory and Advanced Methods, Cambridge University Press.","DOI":"10.1017\/CBO9780511609633"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18272","DOI":"10.1039\/D0CP03145C","article-title":"Intra- and intermolecular atomic-scale interactions in the receptor binding domain of SARS-CoV-2 spike protein: Implication for ACE2 receptor binding","volume":"22","author":"Adhikari","year":"2020","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.csbj.2021.02.004","article-title":"Ultra-Large-Scale Ab Initio Quantum Chemical Computation of Bio-Molecular Systems: The Case of Spike Protein of SARS-CoV-2 Virus","volume":"19","author":"Ching","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4425","DOI":"10.1021\/acs.jcim.1c00560","article-title":"Key interacting residues between RBD of SARS-CoV-2 and ACE2 receptor: Combination of molecular dynamic simulation and density functional calculation","volume":"61","author":"Jawad","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Adhikari, P., Podgornik, R., Jawad, B., and Ching, W.-Y. (2021). First-Principles Simulation of Dielectric Function in Biomolecules. Materials, 14.","DOI":"10.3390\/ma14195774"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Baral, K., Adhikari, P., Jawad, B., Podgornik, R., and Ching, W.-Y. (2021). Solvent Effect on the Structure and Properties of RGD Peptide (1FUV) at Body Temperature (310 K) Using Ab Initio Molecular Dynamics. Polymers, 13.","DOI":"10.3390\/polym13193434"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"024201","DOI":"10.1103\/PhysRevB.83.024201","article-title":"Ab initio investigation of hydrogen bonding and network structure in a supercooled model of water","volume":"83","author":"Liang","year":"2011","journal-title":"Phys. Rev. B"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7074","DOI":"10.1002\/chem.202004653","article-title":"Not Carbon s\u2013p Hybridization, but Coordination Number Determines C\u2212H and C\u2212C Bond Length","volume":"27","author":"Vermeeren","year":"2021","journal-title":"Chem. A Eur. J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/s41586-021-03944-y","article-title":"SARS-CoV-2 B. 1.617. 2 Delta variant replication and immune evasion","volume":"599","author":"Mlcochova","year":"2021","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1056\/NEJMoa2108891","article-title":"Effectiveness of COVID-19 vaccines against the B. 1.617. 2 (Delta) variant","volume":"385","author":"Andrews","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"102715","DOI":"10.1016\/j.jaut.2021.102715","article-title":"Evolutionary analysis of the Delta and Delta Plus variants of the SARS-CoV-2 viruses","volume":"124","author":"Kannan","year":"2021","journal-title":"J. Autoimmun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e108944","DOI":"10.15252\/embj.2021108944","article-title":"SARS-CoV-2 Alpha, Beta, and Delta variants display enhanced Spike-mediated syncytia formation","volume":"40","author":"Rajah","year":"2021","journal-title":"EMBO J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/s41576-021-00408-x","article-title":"The biological and clinical significance of emerging SARS-CoV-2 variants","volume":"22","author":"Tao","year":"2021","journal-title":"Nat. Rev. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.meegid.2014.12.022","article-title":"Recombination in viruses: Mechanisms, methods of study, and evolutionary consequences","volume":"30","author":"Arenas","year":"2015","journal-title":"Infect. Genet. Evol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nrg2323","article-title":"Rates of evolutionary change in viruses: Patterns and determinants","volume":"9","author":"Duffy","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3134","DOI":"10.1128\/JVI.01394-09","article-title":"Recombination, reservoirs, and the modular spike: Mechanisms of coronavirus cross-species transmission","volume":"84","author":"Graham","year":"2010","journal-title":"J. Virol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1038\/s41564-020-0771-4","article-title":"Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic","volume":"5","author":"Boni","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41579-021-00573-0","article-title":"SARS-CoV-2 variants, spike mutations and immune escape","volume":"19","author":"Harvey","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_63","unstructured":"(The Economist, 2021). On the origin of Species, The Economist."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.cell.2020.09.032","article-title":"Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant","volume":"183","author":"Yurkovetskiy","year":"2020","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1126\/science.abi5052","article-title":"Making machine learning trustworthy","volume":"373","author":"Eshete","year":"2021","journal-title":"Science"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1145\/3134599","article-title":"Making machine learning robust against adversarial inputs","volume":"61","author":"Goodfellow","year":"2018","journal-title":"Commun. ACM"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"James, G., Witten, D., Hastie, T., and Tibshirani, R. (2013). An Introduction to Statistical Learning with Applications in R, Springer.","DOI":"10.1007\/978-1-4614-7138-7"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/BF00994018","article-title":"Support-vector networks","volume":"20","author":"Cortes","year":"1995","journal-title":"Mach. Learn."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/BF00116251","article-title":"Induction of decision trees","volume":"1","author":"Quinlan","year":"1986","journal-title":"Mach. Learn."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random Forests","volume":"45","author":"Breiman","year":"2001","journal-title":"Mach. Learn."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Chen, T., and Guestrin, C. (2016, January 13). Xgboost: A scalable tree boosting system. Proceedings of the 22nd ACM SIGKDD International Conference on Knowledge Discovery and Data Mining, New York, NY, USA.","DOI":"10.1145\/2939672.2939785"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s10994-006-5833-1","article-title":"Markov logic networks","volume":"62","author":"Richardson","year":"2006","journal-title":"Mach. Learn."},{"key":"ref_73","unstructured":"Pearl, J. (2000). Causality: Models, Reasoning and Inference, Cambridge University Press."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s10994-006-6889-7","article-title":"The max-min hill-climbing Bayesian network structure learning algorithm","volume":"65","author":"Tsamardinos","year":"2006","journal-title":"Mach. Learn."},{"key":"ref_75","unstructured":"(2021, November 28). Classification of Omicron (B.1.1.529): SARS-CoV-2 Variant of Concern. Available online: https:\/\/www.who.int\/news\/item\/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern."},{"key":"ref_76","unstructured":"(2021, November 28). NERSC Perlmutter, Available online: https:\/\/www.nersc.gov\/systems\/perlmutter\/."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1103\/PhysRevLett.77.3865","article-title":"Generalized gradient approximation made simple","volume":"77","author":"Perdew","year":"1996","journal-title":"Phys. Rev. Lett."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"21573","DOI":"10.1039\/C6CP04357G","article-title":"Implication of the solvent effect, metal ions and topology in the electronic structure and hydrogen bonding of human telomeric G-quadruplex DNA","volume":"18","author":"Poudel","year":"2016","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"6321","DOI":"10.1021\/acs.jpcb.7b02569","article-title":"Impact of hydrogen bonding in the binding site between capsid protein and MS2 bacteriophage ssRNA","volume":"121","author":"Poudel","year":"2017","journal-title":"J. Phys. Chem. B"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1002\/qua.25089","article-title":"Charge distribution and hydrogen bonding of a collagen \u03b12-chain in vacuum, hydrated, neutral, and charged structural models","volume":"116","author":"Eifler","year":"2016","journal-title":"Int. J. Quantum Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1002\/cphc.201402893","article-title":"Electronic structure and partial charge distribution of doxorubicin in different molecular environments","volume":"16","author":"Poudel","year":"2015","journal-title":"ChemPhysChem"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"022705","DOI":"10.1103\/PhysRevE.90.022705","article-title":"Electronic structure, stacking energy, partial charge, and hydrogen bonding in four periodic B-DNA models","volume":"90","author":"Poudel","year":"2014","journal-title":"Phys. Rev. E"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"15362","DOI":"10.1021\/acs.jpcc.6b06337","article-title":"Structure and electronic properties of a continuous random network model of an amorphous zeolitic imidazolate framework (a-ZIF)","volume":"120","author":"Adhikari","year":"2016","journal-title":"J. Phys. Chem. C"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1111\/jace.15538","article-title":"First-principles study in an inter-granular glassy film model of silicon nitride","volume":"101","author":"Ching","year":"2018","journal-title":"J. Am. Ceram. Soc."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41524-020-0321-x","article-title":"Fundamental electronic structure and multiatomic bonding in 13 biocompatible high-entropy alloys","volume":"6","author":"Ching","year":"2020","journal-title":"npj Comput. Mater."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7803","DOI":"10.1021\/acs.jpcb.0c05840","article-title":"Thermodynamic Dissection of the Intercalation Binding Process of Doxorubicin to dsDNA with Implications of Ionic and Solvent Effects","volume":"124","author":"Jawad","year":"2020","journal-title":"J. Phys. Chem. B"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"8418","DOI":"10.1021\/acs.jpcb.0c05875","article-title":"Ab Initio Study of Hydrolysis Effects in Single and Ion-Exchanged Alkali Aluminosilicate Glasses","volume":"124","author":"Baral","year":"2020","journal-title":"J. Phys. Chem. B"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1063\/1.1740588","article-title":"Electronic population analysis on LCAO\u2013MO molecular wave functions. I","volume":"23","author":"Mulliken","year":"1955","journal-title":"J. Chem. Phys."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1063\/1.1740589","article-title":"Electronic population analysis on LCAO\u2013MO molecular wave functions. II. Overlap populations, bond orders, and covalent bond energies","volume":"23","author":"Mulliken","year":"1955","journal-title":"J. Chem. Phys."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/3\/465\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:26:43Z","timestamp":1760135203000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/3\/465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,24]]},"references-count":89,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["v14030465"],"URL":"https:\/\/doi.org\/10.3390\/v14030465","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.12.01.470802","asserted-by":"object"}]},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,24]]}}}