Principles for computational design of binding antibodies
Open accessAbstract
Significance: Antibodies are the most versatile class of binding molecule known, and have numerous applications in biomedicine. Computational design of antibodies, however, poses unusual difficulties relative to previously designed proteins, as antibodies comprise multiple nonideal features, such as long and unstructured loops and buried charges and polar interaction networks. We developed an algorithm that uses information on backbone conformations and sequence-conservation patterns observed in natural antibodies to design new antibody binders. Designed antibodies were very different in sequence from natural ones, but had similarly desirable properties of affinity and stability, and molecular structures showed high accuracy relative to the design models. The design principles we implemented can be used to design other functional folds, including many enzyme classes.
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Designing proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains a challenge.
“The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains a challenge1–5.”
From Design of protein-binding proteins from the target structure alone (2022) · cites this paper as [4]
Computational docking of antibody scaffolds with varied loop geometries has yielded binders, but the designed binding modes have rarely been validated with high-resolution structures.
“Computational docking of antibody scaffolds with varied loop geometries has yielded binders, but the designed binding modes have rarely been validated with high-resolution structures4.”
From Design of protein-binding proteins from the target structure alone (2022) · cites this paper as [4]
Established structural bioinformatics methods such as homology modelling, protein-protein docking or protein interface prediction are already used for rational antibody design.
“Established structural bioinformatics methods such as homology modelling [6, 7], protein–protein docking [8, 9] or protein interface prediction [10] are already used for rational antibody design [11–13].”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [12]
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- Authors
- Baran, D., Pszolla, M. G., Lapidoth, G. D., Norn, C., Dym, O., Unger, T., Albeck, S., Tyka, M. D., & Fleishman, S. J.
- Affiliations
- Weizmann Institute of Science (IL)
- Google (United States) (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-09-25
- Volume
- 114
- Issue
- 41
- Pages
- 10900-10905
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5642698
- OpenAlex
- W2758496793
- Cited by
- 136
- References
- 51
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 12 · 2023: 13 · 2022: 20 · 2021: 28 · 2020: 14 · 2019: 16 · 2018: 15
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- antibody design, computational protein design, binding antibodies, sequence conservation, backbone conformation, natural antibodies, buried charges, affinity, stability, enzyme design
- MeSH terms
- Antibodies, Binding Sites, Antibody, Humans, Immunoglobulin Fragments, Insulin, Ligands, Models, Molecular, Mycobacterium tuberculosis, Protein Conformation, Crystallography, X-Ray, Complementarity Determining Regions, Acyl-Carrier Protein S-Acetyltransferase
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