{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T05:38:14Z","timestamp":1762234694199,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People\u2019s Republic of China","doi-asserted-by":"crossref","award":["2023YFD1700500"],"award-info":[{"award-number":["2023YFD1700500"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The ongoing evolution of SARS-CoV-2 has given rise to variants with enhanced transmissibility and pathogenicity, many of which harbor mutations in the receptor-binding domain (RBD) of the viral spike protein. These mutations often confer increased viral fitness and immune evasion by modulating interactions with the human ACE2 receptor (hACE2) and escaping neutralizing antibodies. Accurate prediction of the functional consequences of such mutations\u2014particularly their effects on receptor binding and antibody escape\u2014is critical for assessing the public health threat posed by emerging variants. In this study, we apply a Mutation-dependent Biomacromolecular Quantitative Structure\u2013Activity Relationship (MB-QSAR) framework to quantitatively model the biochemical phenotypes of RBD variants. Trained on comprehensive deep mutational scanning (DMS) datasets, our models exhibit strong predictive performance, achieving correlation coefficients (r2) exceeding 0.8 for hACE2 binding affinity and 0.7 for antibody neutralization escape. Importantly, the MB-QSAR approach generalizes well to multi-mutant variants and currently circulating lineages. Structural analysis based on model-derived interaction profiles offers mechanistic insights into key RBD\u2013ACE2 and RBD\u2013antibody interfaces, helping the rational design of broadly protective vaccines and therapeutics. This work establishes MB-QSAR as a rapid, accurate, and interpretable tool for the prediction of protein\u2013protein interaction and forecasting viral adaptation, thereby facilitating early risk assessment of novel SARS-CoV-2 variants.<\/jats:p>","DOI":"10.3390\/biom15111538","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:47:58Z","timestamp":1762177678000},"page":"1538","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modeling the Mutational Effects on Biochemical Phenotypes of SARS-CoV-2 Using Molecular Fields"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0887-5795","authenticated-orcid":false,"given":"Baifan","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Elemento-Organic Chemistry, Department of Chemical Biology, National Pesticide Engineering Research Center (Tianjin), Nankai University, Tianjin 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Xi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Elemento-Organic Chemistry, Department of Chemical Biology, National Pesticide Engineering Research Center (Tianjin), Nankai University, Tianjin 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/s41591-020-0863-y","article-title":"If the world fails to protect the economy, COVID-19 will damage health not just now but also in the future","volume":"26","author":"McKee","year":"2020","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1126\/science.abc3189","article-title":"Ecology and economics for pandemic prevention","volume":"369","author":"Dobson","year":"2020","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1093\/bioinformatics\/btab856","article-title":"CoV-Spectrum: Analysis of globally shared SARS-CoV-2 data to identify and characterize new variants","volume":"38","author":"Chen","year":"2022","journal-title":"Bioinformatics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1038\/s41591-022-01911-2","article-title":"Emergence of SARS-CoV-2 omicron lineages BA. 4 and BA. 5 in South Africa","volume":"28","author":"Tegally","year":"2022","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/S1473-3099(23)00010-5","article-title":"ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5","volume":"23","author":"Yue","year":"2023","journal-title":"Lancet Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/s41421-024-00752-2","article-title":"Structural and molecular basis of the epistasis effect in enhanced affinity between SARS-CoV-2 KP.3 and ACE2","volume":"10","author":"Feng","year":"2024","journal-title":"Cell Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e6","DOI":"10.1016\/S1473-3099(24)00738-2","article-title":"Enhanced immune evasion of SARS-CoV-2 variants KP.3.1.1 and XEC through N-terminal domain mutations","volume":"25","author":"Liu","year":"2025","journal-title":"Lancet Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/s41586-021-03324-6","article-title":"mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants","volume":"592","author":"Wang","year":"2021","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S0966-842X(00)01830-8","article-title":"Viral mechanisms of immune evasion","volume":"8","author":"Alcami","year":"2000","journal-title":"Trends. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S2213-2600(21)00075-8","article-title":"SARS-CoV-2 evolution and vaccines: Cause for concern?","volume":"9","author":"Williams","year":"2021","journal-title":"Lancet Respir. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e732","DOI":"10.1016\/S1473-3099(24)00688-1","article-title":"Impact of JN.1 booster vaccination on neutralisation of SARS-CoV-2 variants KP.3.1.1 and XEC","volume":"24","author":"Arora","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"veae067","DOI":"10.1093\/ve\/veae067","article-title":"Deep mutational scanning of SARS-CoV-2 Omicron BA.2.86 and epistatic emergence of the KP.3 variant","volume":"10","author":"Taylor","year":"2024","journal-title":"Virus Evol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41579-020-00468-6","article-title":"Coronavirus biology and replication: Implications for SARS-CoV-2","volume":"19","author":"Kratzel","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.cell.2020.03.045","article-title":"Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2","volume":"181","author":"Wang","year":"2020","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/s41586-020-2514-3","article-title":"Structures of fungal and plant acetohydroxyacid synthases","volume":"586","author":"Lonhienne","year":"2020","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/s41586-020-2180-5","article-title":"Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor","volume":"581","author":"Lan","year":"2020","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.cell.2020.05.025","article-title":"Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients\u2019 B Cells","volume":"182","author":"Cao","year":"2020","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41586-020-2381-y","article-title":"A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2","volume":"584","author":"Shi","year":"2020","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1126\/science.abd0827","article-title":"Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail","volume":"369","author":"Hansen","year":"2020","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s41586-020-2380-z","article-title":"Human neutralizing antibodies elicited by SARS-CoV-2 infection","volume":"584","author":"Ju","year":"2020","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"eabg3055","DOI":"10.1126\/science.abg3055","article-title":"Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England","volume":"372","author":"Davies","year":"2021","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/j.cell.2020.07.012","article-title":"The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity","volume":"182","author":"Li","year":"2020","journal-title":"Cell"},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.cell.2020.09.037","article-title":"Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology","volume":"183","author":"Piccoli","year":"2020","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1126\/science.abf9302","article-title":"Prospective mapping of viral mutations that escape antibodies used to treat COVID-19","volume":"371","author":"Starr","year":"2021","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.chom.2020.11.007","article-title":"Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition","volume":"29","author":"Greaney","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1016\/j.cell.2020.08.012","article-title":"Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding","volume":"182","author":"Starr","year":"2020","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1016\/S1473-3099(21)00007-4","article-title":"First detection of SARS-CoV-2 spike protein N501 mutation in Italy in August, 2020","volume":"21","author":"Fiorentini","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41586-021-03470-x","article-title":"Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England","volume":"593","author":"Volz","year":"2021","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/s41586-021-03402-9","article-title":"Detection of a SARS-CoV-2 variant of concern in South Africa","volume":"592","author":"Tegally","year":"2021","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/s41591-021-01255-3","article-title":"Sixteen novel lineages of SARS-CoV-2 in South Africa","volume":"27","author":"Tegally","year":"2021","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1056\/NEJMc2104192","article-title":"Cross-Reactive Neutralizing Antibody Responses Elicited by SARS-CoV-2 501Y.V2 (B.1.351)","volume":"384","author":"Madzivhandila","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/s41591-021-01318-5","article-title":"Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies","volume":"27","author":"Planas","year":"2021","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2106480118","DOI":"10.1073\/pnas.2106480118","article-title":"Computational prediction of the effect of amino acid changes on the binding affinity between SARS-CoV-2 spike RBD and human ACE2","volume":"118","author":"Chen","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhou, W., Xu, C., Wang, P., Luo, M., Xu, Z., Cheng, R., Jin, X., Guo, Y., Xue, G., and Juan, L. (2021). N439K Variant in Spike Protein Alter the Infection Efficiency and Antigenicity of SARS-CoV-2 Based on Molecular Dynamics Simulation. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.697035"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5212","DOI":"10.1016\/j.jmb.2020.07.009","article-title":"Mutations Strengthened SARS-CoV-2 Infectivity","volume":"432","author":"Chen","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6929","DOI":"10.1021\/acsnano.0c10833","article-title":"Computational Mutagenesis at the SARS-CoV-2 Spike Protein\/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison with Experimental Evidence","volume":"15","author":"Laurini","year":"2021","journal-title":"ACS Nano"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.biochi.2020.11.004","article-title":"Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 Spike protein","volume":"180","author":"Calcagnile","year":"2021","journal-title":"Biochimie"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1038\/s41591-023-02483-5","article-title":"Deep-learning-enabled protein-protein interaction analysis for prediction of SARS-CoV-2 infectivity and variant evolution","volume":"29","author":"Wang","year":"2023","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1002\/cjoc.201300417","article-title":"Molecular Drug Resistance Prediction for Acetohydroxyacid Synthase Mutants Against Chlorsulfuron Using MB-QSAR","volume":"31","author":"He","year":"2013","journal-title":"Chin. J. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/minf.201200144","article-title":"Biomacromolecular 3D-QSAR to Decipher Molecular Herbicide Resistance in Acetohydroxyacid Synthases","volume":"32","author":"He","year":"2013","journal-title":"Mol. Inform."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12729","DOI":"10.1021\/acs.jafc.0c04947","article-title":"Comparative studies of potential binding pocket residues reveal the molecular basis of ShHTL receptors in the perception of GR24 in Striga","volume":"68","author":"Pang","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"141","DOI":"10.6023\/A21110526","article-title":"Prediction on the resistance of acetohydroxyacid synthase mutants to herbicide flumetsulam","volume":"80","author":"Wang","year":"2022","journal-title":"Acta Chim. Sin."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Wang, B., He, Y., Wen, X., and Xi, Z. (2022). Prediction and molecular field view of drug resistance in HIV-1 protease mutants. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-07012-x"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1126\/science.abc0870","article-title":"Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2","volume":"369","author":"Chan","year":"2020","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4196","DOI":"10.1038\/s41467-021-24435-8","article-title":"Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies","volume":"12","author":"Greaney","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"100255","DOI":"10.1016\/j.xcrm.2021.100255","article-title":"Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016","volume":"2","author":"Starr","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/s41586-021-03807-6","article-title":"SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape","volume":"597","author":"Starr","year":"2021","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1038\/s41564-021-00972-2","article-title":"Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail","volume":"6","author":"Dong","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/s41586-021-03817-4","article-title":"Broad sarbecovirus neutralization by a human monoclonal antibody","volume":"597","author":"Tortorici","year":"2021","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5.6.1","DOI":"10.1002\/cpbi.3","article-title":"Comparative Protein Structure Modeling Using MODELLER","volume":"54","author":"Webb","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5959","DOI":"10.1021\/ja00226a005","article-title":"Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins","volume":"110","author":"Cramer","year":"1988","journal-title":"J. Am. Chem. Soc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4130","DOI":"10.1021\/jm00050a010","article-title":"Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity","volume":"37","author":"Klebe","year":"1994","journal-title":"J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1038\/s41564-021-00954-4","article-title":"SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution","volume":"6","author":"Marciano","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/s41586-021-04386-2","article-title":"Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift","volume":"602","author":"Cameroni","year":"2022","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.chom.2021.01.014","article-title":"Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization","volume":"29","author":"Liu","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/s41586-021-03471-w","article-title":"Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma","volume":"593","author":"Cele","year":"2021","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.chom.2021.02.003","article-title":"Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies","volume":"29","author":"Greaney","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"15207","DOI":"10.1080\/07391102.2023.2194007","article-title":"Comprehensive deep mutational scanning reveals the pH induced stability and binding differences between SARS-CoV-2 spike RBD and human ACE2","volume":"41","author":"Haque","year":"2023","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Xie, Y., Guo, W., Lopez-Hernadez, A., Teng, S., and Li, L. (2022). The pH Effects on SARS-CoV and SARS-CoV-2 Spike Proteins in the Process of Binding to hACE2. Pathogens, 11.","DOI":"10.3390\/pathogens11020238"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.chom.2020.11.004","article-title":"Cryo-EM Structures of SARS-CoV-2 Spike without and with ACE2 Reveal a pH-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains","volume":"28","author":"Zhou","year":"2020","journal-title":"Cell Host Microbe"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1538\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T05:34:07Z","timestamp":1762234447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1538"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,31]]},"references-count":61,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["biom15111538"],"URL":"https:\/\/doi.org\/10.3390\/biom15111538","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2025,10,31]]}}}