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Mimotope-Guided Molecular Dynamics Enables Precise Functional Epitope Mapping.

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Τίτλος: Mimotope-Guided Molecular Dynamics Enables Precise Functional Epitope Mapping.
Συγγραφείς: Sha Z; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China., Hu Z; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China., Du W; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China., Marti J; Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B4-B5 Northern Campus, Barcelona, Catalonia08034, Spain., Sundell GN; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China.; TongRen Hospital, Shanghai Jiao Tong University School of Medicine, No. 1111 Xianxia Road, Changning District, Shanghai200000, China., Guo SJ; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China., Zhao X; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China., Tao SC; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China.
Πηγή: Journal of chemical information and modeling [J Chem Inf Model] 2026 Sep 14; Vol. 66 (17), pp. 11259-11274.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101230060 Publication Model: Print Cited Medium: Internet ISSN: 1549-960X (Electronic) Linking ISSN: 15499596 NLM ISO Abbreviation: J Chem Inf Model Subsets: MEDLINE
Imprint Name(s): Original Publication: Washington, D.C. : American Chemical Society, c2005-
Ιατρικοί όροι (MeSH): Epitope Mapping*/methods , Epitopes*/chemistry , Epitopes*/immunology , Molecular Dynamics Simulation*, Protein Conformation
Περίληψη: Mimotopes selected by phage display have been used for antibody epitope mapping for nearly four decades, but residue-level recovery of functional epitopes has remained unreliable. This is not a problem of algorithms but of assumptions: mimotopes recapitulate native epitope recognition through compensatory interaction networks that preserve binding energetics, without conserving sequence or surface geometry. Predictors trained on sequence similarity or static interface geometry therefore miss the residues that drive recognition. We present a physics-based workflow that refines antibody-bound mimotope conformations by microsecond-scale molecular dynamics and maps the resulting structures onto the cognate antigen using Folddisco. Across four antibody-antigen systems with crystallographically defined epitopes, the workflow reaches 60 to 100% precision in epitope localization and recovers 100% of mutagenesis- or structurally validated functional hotspots, compared with at most 25% for three widely used benchmarks (EpiSearch, ClusPro, SEPPA-mAb). For the clinically relevant ChiLob 7/4 system, it further identifies a minimal tetrapeptide (PWVP) sufficient for antibody recognition, validated by Western blot and immunoprecipitation. By grounding epitope prediction in experimentally selected binding information and energy-resolved conformational refinement, the workflow connects phage display to mechanistic structural insight.
(© 2026 American Chemical Society.)
Grant Information: NA Ministerio de Ciencia, Innovaci?n y Universidades; 32571104 National Natural Science Foundation of China; 92374110 National Natural Science Foundation of China; 2021SGR-01411 Generalitat de Catalunya; 2026M792926 China Postdoctoral Science Foundation; NA European Regional Development Fund; PID2021-124297NB-C32 Agencia Estatal de Investigaci?n; PID2024-157478NB-C32 Agencia Estatal de Investigaci?n; 2023YFC2307200 National Key Research and Development Program of China; 2024YFA1307600 National Key Research and Development Program of China; 2024YFA1307601 National Key Research and Development Program of China; 2024YFA1307602 National Key Research and Development Program of China; 2024YFA1307603 National Key Research and Development Program of China; 2024YFA1307604 National Key Research and Development Program of China; YG2023ZD04 Fundamental Research Funds for the Central Universities; NA Universitat Polit?cnica de Catalunya; GZNL2023A01005 National Science and Technology Major Project
Substance Nomenclature: 0 (Epitopes)
Entry Date(s): Date Created: 20260914 Date Completed: 20260914 Latest Revision: 20260914
Update Code: 20260914
DOI: 10.1021/acs.jcim.6c01562
PMID: 42734546
Βάση Δεδομένων: MEDLINE
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PubType: Academic Journal
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  Data: Mimotope-Guided Molecular Dynamics Enables Precise Functional Epitope Mapping.
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  Data: <searchLink fieldCode="AU" term="%22Sha+Z%22">Sha Z</searchLink>; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China.<br /><searchLink fieldCode="AU" term="%22Hu+Z%22">Hu Z</searchLink>; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China.<br /><searchLink fieldCode="AU" term="%22Du+W%22">Du W</searchLink>; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China.<br /><searchLink fieldCode="AU" term="%22Marti+J%22">Marti J</searchLink>; Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B4-B5 Northern Campus, Barcelona, Catalonia08034, Spain.<br /><searchLink fieldCode="AU" term="%22Sundell+GN%22">Sundell GN</searchLink>; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China.; TongRen Hospital, Shanghai Jiao Tong University School of Medicine, No. 1111 Xianxia Road, Changning District, Shanghai200000, China.<br /><searchLink fieldCode="AU" term="%22Guo+SJ%22">Guo SJ</searchLink>; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China.<br /><searchLink fieldCode="AU" term="%22Zhao+X%22">Zhao X</searchLink>; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China.<br /><searchLink fieldCode="AU" term="%22Tao+SC%22">Tao SC</searchLink>; Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang, Shanghai200240, China.
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  Data: <searchLink fieldCode="JN" term="%22101230060%22">Journal of chemical information and modeling</searchLink> [J Chem Inf Model] 2026 Sep 14; Vol. 66 (17), pp. 11259-11274.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22American+Chemical+Society%22">American Chemical Society </searchLink><i>Country of Publication: </i>United States <i>NLM ID: </i>101230060 <i>Publication Model: </i>Print <i>Cited Medium: </i>Internet <i>ISSN: </i>1549-960X (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2215499596%22">15499596 </searchLink><i>NLM ISO Abbreviation: </i>J Chem Inf Model <i>Subsets: </i>MEDLINE
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  Data: <i>Original Publication</i>: Washington, D.C. : American Chemical Society, c2005-
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  Label: Abstract
  Group: Ab
  Data: Mimotopes selected by phage display have been used for antibody epitope mapping for nearly four decades, but residue-level recovery of functional epitopes has remained unreliable. This is not a problem of algorithms but of assumptions: mimotopes recapitulate native epitope recognition through compensatory interaction networks that preserve binding energetics, without conserving sequence or surface geometry. Predictors trained on sequence similarity or static interface geometry therefore miss the residues that drive recognition. We present a physics-based workflow that refines antibody-bound mimotope conformations by microsecond-scale molecular dynamics and maps the resulting structures onto the cognate antigen using Folddisco. Across four antibody-antigen systems with crystallographically defined epitopes, the workflow reaches 60 to 100% precision in epitope localization and recovers 100% of mutagenesis- or structurally validated functional hotspots, compared with at most 25% for three widely used benchmarks (EpiSearch, ClusPro, SEPPA-mAb). For the clinically relevant ChiLob 7/4 system, it further identifies a minimal tetrapeptide (PWVP) sufficient for antibody recognition, validated by Western blot and immunoprecipitation. By grounding epitope prediction in experimentally selected binding information and energy-resolved conformational refinement, the workflow connects phage display to mechanistic structural insight.<br /> (© 2026 American Chemical Society.)
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  Data: NA Ministerio de Ciencia, Innovaci?n y Universidades; 32571104 National Natural Science Foundation of China; 92374110 National Natural Science Foundation of China; 2021SGR-01411 Generalitat de Catalunya; 2026M792926 China Postdoctoral Science Foundation; NA European Regional Development Fund; PID2021-124297NB-C32 Agencia Estatal de Investigaci?n; PID2024-157478NB-C32 Agencia Estatal de Investigaci?n; 2023YFC2307200 National Key Research and Development Program of China; 2024YFA1307600 National Key Research and Development Program of China; 2024YFA1307601 National Key Research and Development Program of China; 2024YFA1307602 National Key Research and Development Program of China; 2024YFA1307603 National Key Research and Development Program of China; 2024YFA1307604 National Key Research and Development Program of China; YG2023ZD04 Fundamental Research Funds for the Central Universities; NA Universitat Polit?cnica de Catalunya; GZNL2023A01005 National Science and Technology Major Project
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