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Due to involving high-throughput screens, biological experiments for antibody affinity maturation are time-consuming and have a low success rate. Precise computational-assisted antibody design promises to accelerate this process, but there is still a lack of effective computational methods capable of pinpointing beneficial mutations within the complementarity-determining region (CDR) of antibodies. Moreover, random mutations often lead to challenges in antibody expression and immunogenicity. In this study, to enhance the affinity of a human antibody against avian influenza virus, a CDR library was constructed and evolutionary information was acquired through sequence alignment to restrict the mutation positions and types. Concurrently, a statistical potential methodology was developed based on amino acid interactions between antibodies and antigens to calculate potential affinity-enhanced antibodies, which were further subjected to molecular dynamics simulations. Subsequently, experimental validation confirmed that a point mutation enhancing 2.5-fold affinity was obtained from 10 designs, resulting in the antibody affinity of 2\u00a0nM. A predictive model for antibody\u2013antigen interactions based on the binding interface was also developed, achieving an Area Under the Curve (AUC) of 0.83 and a precision of 0.89 on the test set. Lastly, a novel approach involving combinations of affinity-enhancing mutations and an iterative mutation optimization scheme similar to the Monte Carlo method were proposed. This study presents computational methods that rapidly and accurately enhance antibody affinity, addressing issues related to antibody expression and immunogenicity.<\/jats:p>","DOI":"10.1093\/bib\/bbae488","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T00:29:12Z","timestamp":1727915352000},"source":"Crossref","is-referenced-by-count":11,"title":["Development and experimental validation of computational methods for human antibody affinity enhancement"],"prefix":"10.1093","volume":"25","author":[{"given":"Junxin","family":"Li","sequence":"first","affiliation":[{"name":"Center for Protein and Cell-based Drugs , Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, , 1068 Xueyuan Avenue, Nanshan District, Shenzhen 518055,","place":["China"]},{"name":"Chinese Academy of Sciences , Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, , 1068 Xueyuan Avenue, Nanshan District, Shenzhen 518055,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linbu","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Computational Biomedicine, Cedars-Sinai Medical Center , 8700 Beverly Blvd, Los Angeles, CA 90048,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Quantitative Synthetic Biology , Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Avenue, Nanshan District, Shenzhen 518055,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaifang","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Quantitative Synthetic Biology , Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Avenue, Nanshan District, Shenzhen 518055,","place":["China"]},{"name":"School of Chemistry and Molecular Engineering, East China Normal University , 3663 Zhongshan North Road, Putuo District, Shanghai 200062,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory of Nanomedicine , Shenzhen Engineering Laboratory of Nanomedicine and Nanoformulations, CAS Key Lab for Health Informatics, Shenzhen Institutes of Advanced Technology, , 1068 Xueyuan Avenue, Nanshan District, Shenzhen 518055,","place":["China"]},{"name":"Chinese Academy of Sciences , Shenzhen Engineering Laboratory of Nanomedicine and Nanoformulations, CAS Key Lab for Health Informatics, Shenzhen Institutes of Advanced Technology, , 1068 Xueyuan Avenue, Nanshan District, Shenzhen 518055,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4612-1863","authenticated-orcid":false,"given":"John Z H","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Quantitative Synthetic Biology , Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Avenue, Nanshan District, Shenzhen 518055,","place":["China"]},{"name":"Faculty of Synthetic Biology , Shenzhen University of Advanced Technology, Shenzhen 518055,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaochun","family":"Wan","sequence":"additional","affiliation":[{"name":"Center for Protein and Cell-based Drugs , Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, , 1068 Xueyuan Avenue, Nanshan District, Shenzhen 518055,","place":["China"]},{"name":"Chinese Academy of Sciences , Institute 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