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Antibody evolution constrains conformational heterogeneity by tailoring protein dynamics
Open accessAbstract
The evolution of proteins with novel function is thought to start from precursor proteins that are conformationally heterogeneous. The corresponding genes may be duplicated and then mutated to select and optimize a specific conformation. However, testing this idea has been difficult because of the challenge of quantifying protein flexibility and conformational heterogeneity as a function of evolution. Here, we report the characterization of protein heterogeneity and dynamics as a function of evolution for the antifluorescein antibody 4-4-20. Using nonlinear laser spectroscopy, surface plasmon resonance, and molecular dynamics simulations, we demonstrate that evolution localized the Ab-combining site from a heterogeneous ensemble of conformations to a single conformation by introducing mutations that act cooperatively and over significant distances to rigidify the protein. This study demonstrates how protein dynamics may be tailored by evolution and has important implications for our understanding of how novel protein functions are evolved.
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“Controlled evolution of the antifluorescein antibody 4–4-20 localized the Ab-combining site from a heterogeneous ensemble of conformations to a single conformation by introducing mutations that act cooperatively and over significant distances to rigidify the protein.519”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [519]
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“Antibody evolution may constrain conformational heterogeneity by tailoring protein dynamics.519”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [519]
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Self-citationStructure and Dynamics of Bio- and Macromolecules
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Self-citationDevelopment of a Humanized Antibody 5D3Hu against the PRAME Tumor Antigen
Ларина, М. В., Finashutina, Y. P., Lyzhko, N. A., Misyurin, V. A., Novoseletsky, V. N., Dolgikh, D. A., Солопова, О. Н., Moysenovich, A. M., Сергеевич, Б. Д., Aliev, T. K., et al. (2022) · Russian Journal of Bioorganic Chemistry · doi:10.1134/s1068162022020133 · Cited by 1
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Self-citationFrustration and fuzziness in the three functional states of proteins
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Profiling Hinge Plasticity in Intact Monoclonal Antibodies for Antigen Recognition
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Metadata
- Authors
- Zimmermann, J., Oakman, E. L., Thorpe, I. F., Shi, X., Abbyad, P., Brooks, C. L., Boxer, S. G., & Romesberg, F. E.
- Affiliations
- Departments of *Chemistry and
- University of California San Diego (US)
- Scripps Research Institute (US)
- Stanford University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-09-12
- Volume
- 103
- Issue
- 37
- Pages
- 13722-13727
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1564241
- OpenAlex
- W2132524280
- Cited by
- 116
- References
- 46
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2022: 10 · 2021: 3 · 2020: 4 · 2019: 6 · 2018: 7 · 2017: 3 · 2016: 4 · 2015: 8 · 2014: 8 · 2013: 6 · 2012: 11
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- antibody evolution, conformational heterogeneity, protein dynamics, combining site, protein flexibility
- MeSH terms
- Animals, Antibodies, Humans, Immunoglobulin Fab Fragments, Mutation, Protein Conformation, Proteins, Evolution, Molecular, Fluorescein, Surface Plasmon Resonance
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