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In silico design of stable single-domain antibodies with high affinity

Zhongyao Zhang, Rob van der Kant, Iva Marković (UGent) , David Vizarraga, Teresa Garcia, Katerina Maragkou, Javier Delgado Blanco, Damiano Cianferoni, Gabriele Orlando, Gabriel Cia, et al.
(2026) STRUCTURE. 34(3). p.404-413
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Abstract
Designing antibodies is complex and resource intensive. While deep learning and generative approaches have shown promise in the design of protein binders, achieving high affinity and stability remains challenging. We introduce EvolveX, a structure-based antibody design pipeline leveraging the empirical force field FoldX to design complementarity-determining regions (CDRs) of single-domain antibodies (VHHs). We demonstrate the ability of EvolveX to redesign a VHH targeting mouse Vsig4 (mVsig4) to address two challenges: enhancing stability and affinity for mVsig4 and redesigning it for high affinity to the human ortholog. Notably, EvolveX improved the binding affinity of VHHs to human Vsig4 by over 1,000-fold. Structural analyses by X-ray crystallography confirmed design accuracy. Next-generation sequencing (NGS) analysis further demonstrated the efficiency of FoldX-based design pipeline. Collectively, our study highlights EvolveX's potential to overcome current limitations in antibody design, offering a powerful tool for the development of therapeutics with enhanced specificity, stability, and efficacy.
Keywords
- PREDICTION, AGGREGATION, RELAXATION, REFINEMENT, PROTEINS, MODEL

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MLA
Zhang, Zhongyao, et al. “In Silico Design of Stable Single-Domain Antibodies with High Affinity.” STRUCTURE, vol. 34, no. 3, 2026, pp. 404–13, doi:10.1016/j.str.2025.12.010.
APA
Zhang, Z., van der Kant, R., Marković, I., Vizarraga, D., Garcia, T., Maragkou, K., … Rousseau, F. (2026). In silico design of stable single-domain antibodies with high affinity. STRUCTURE, 34(3), 404–413. https://doi.org/10.1016/j.str.2025.12.010
Chicago author-date
Zhang, Zhongyao, Rob van der Kant, Iva Marković, David Vizarraga, Teresa Garcia, Katerina Maragkou, Javier Delgado Blanco, et al. 2026. “In Silico Design of Stable Single-Domain Antibodies with High Affinity.” STRUCTURE 34 (3): 404–13. https://doi.org/10.1016/j.str.2025.12.010.
Chicago author-date (all authors)
Zhang, Zhongyao, Rob van der Kant, Iva Marković, David Vizarraga, Teresa Garcia, Katerina Maragkou, Javier Delgado Blanco, Damiano Cianferoni, Gabriele Orlando, Gabriel Cia, Nick Geukens, Carlo Carolis, Alexander N. Volkov, Savvas Savvides, Maarten Dewilde, Joost Schymkowitz, Luis Serrano Pubul, and Frederic Rousseau. 2026. “In Silico Design of Stable Single-Domain Antibodies with High Affinity.” STRUCTURE 34 (3): 404–413. doi:10.1016/j.str.2025.12.010.
Vancouver
1.
Zhang Z, van der Kant R, Marković I, Vizarraga D, Garcia T, Maragkou K, et al. In silico design of stable single-domain antibodies with high affinity. STRUCTURE. 2026;34(3):404–13.
IEEE
[1]
Z. Zhang et al., “In silico design of stable single-domain antibodies with high affinity,” STRUCTURE, vol. 34, no. 3, pp. 404–413, 2026.
@article{01KMDMEXJQTW8PTM20DF0303ST,
  abstract     = {{Designing antibodies is complex and resource intensive. While deep learning and generative approaches have shown promise in the design of protein binders, achieving high affinity and stability remains challenging. We introduce EvolveX, a structure-based antibody design pipeline leveraging the empirical force field FoldX to design complementarity-determining regions (CDRs) of single-domain antibodies (VHHs). We demonstrate the ability of EvolveX to redesign a VHH targeting mouse Vsig4 (mVsig4) to address two challenges: enhancing stability and affinity for mVsig4 and redesigning it for high affinity to the human ortholog. Notably, EvolveX improved the binding affinity of VHHs to human Vsig4 by over 1,000-fold. Structural analyses by X-ray crystallography confirmed design accuracy. Next-generation sequencing (NGS) analysis further demonstrated the efficiency of FoldX-based design pipeline. Collectively, our study highlights EvolveX's potential to overcome current limitations in antibody design, offering a powerful tool for the development of therapeutics with enhanced specificity, stability, and efficacy.}},
  author       = {{Zhang, Zhongyao and van der Kant, Rob and Marković, Iva and Vizarraga, David and Garcia, Teresa and Maragkou, Katerina and Blanco, Javier Delgado and Cianferoni, Damiano and Orlando, Gabriele and Cia, Gabriel and Geukens, Nick and Carolis, Carlo and Volkov, Alexander N. and Savvides, Savvas and Dewilde, Maarten and Schymkowitz, Joost and Pubul, Luis Serrano and Rousseau, Frederic}},
  issn         = {{0969-2126}},
  journal      = {{STRUCTURE}},
  keywords     = {{- PREDICTION,AGGREGATION,RELAXATION,REFINEMENT,PROTEINS,MODEL}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{404--413}},
  title        = {{In silico design of stable single-domain antibodies with high affinity}},
  url          = {{http://doi.org/10.1016/j.str.2025.12.010}},
  volume       = {{34}},
  year         = {{2026}},
}
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