Thermodynamic Stability and Flexibility Characteristics of Antibody Fragment Complexes
Open accessAbstract
Free energy landscapes, backbone flexibility and residue-residue couplings for being co-rigid or co-flexible are calculated from the minimal Distance Constraint Model (mDCM) on an exploratory dataset consisting of VL, scFv and Fab antibody fragments. Experimental heat capacity curves are reproduced markedly well, and an analysis of quantitative stability/flexibility relationships (QSFR) is applied to a representative VL domain and several complexes in the scFv and Fab forms. Global flexibility in the denatured ensemble typically decreases in the larger complexes due to domain-domain interfaces. Slight decreases in global flexibility also occur in the native state of the larger fragments, but with a concurrent large increase in correlated flexibility. Typically, a VL fragment has more co-rigid residue pairs when isolated compared to the scFv and Fab forms, where correlated flexibility appears upon complex formation. This context dependence on residue- residue couplings in the VL domain across length scales of a complex is consistent with the evolutionary hypothesis of antibody maturation. In comparing two scFv mutants with similar thermodynamic stability, local and long-ranged changes in backbone flexibility are observed. In the case of anti-p24 HIV-1 Fab, a variety of QSFR metrics were found to be atypical, which includes comparatively greater co-flexibility in the VH domain and less co-flexibility in the VL domain. Interestingly, this fragment is the only example of a polyspecific antibody in our dataset. Finally, the mDCM method is extended to cases where thermodynamic data is incomplete, enabling high throughput QSFR studies on large numbers of antibody fragments and their complexes.
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Two scFv mutants with similar thermodynamic stability show local and long-range changes in backbone flexibility.
“In comparing two scFv mutants with similar thermodynamic stability, local and long-ranged changes in backbone flexibility are observed.520”
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 [520]
Correlated flexibility may increase during antibody complex formation.
“It was also found that correlated flexibility may increase during antibody complex formation.520”
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 [520]
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- Authors
- Li, T., Verma, D., Tracka, M., Casas-Finet, J., Livesay, D., & Jacobs, D.
- Affiliations
- University of North Carolina at Charlotte (US)
- Corresponding author
- Livesay, Dennis
- Jacobs, Donald
- Venue
- Protein & Peptide Letters
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2013-07-08
- Volume
- 21
- Issue
- 8
- Pages
- 752-765
- ISSN
- 0929-8665 (ISSN-L)
- PMC
- PMC4667953
- OpenAlex
- W2062727682
- Cited by
- 13
- References
- 1
- Citations by year
- 2023: 1 · 2020: 1 · 2019: 1 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 2
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Protein and Peptide Letters (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (S10 SRR026514)
- National Institute of General Medical Sciences (R01GM073082)
- National Center for Research Resources (S10RR026514)
- 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
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › thermodynamics and calorimetric analyses
- Keywords
- antibody fragments, Fab fragment, scFv fragments, variable light chain, backbone flexibility, free energy landscape, domain-domain interfaces, antibody maturation, polyspecific antibodies
- MeSH terms
- Biomechanical Phenomena, Hot Temperature, Humans, Immunoglobulin Fragments, Models, Molecular, Molecular Weight, Thermodynamics, Protein Structure, Tertiary, Computational Biology, Protein Stability
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