Surprisingly Fast Interface and Elbow Angle Dynamics of Antigen-Binding Fragments
Monica L Fernández-Quintero1, Katharina B Kroell1, Martin C Heiss1
1Center for Molecular Biosciences Innsbruck (CMBI), Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria.
Frontiers in Molecular Biosciences
|December 17, 2020
Summary
Antibody fragments (Fab) show rigidification after affinity maturation and shifts in orientation after humanization. Interface and elbow angle dynamics are crucial for antigen specificity and occur on the nanosecond timescale.
Area of Science:
- Immunology and Structural Biology
- Protein Dynamics and Antibody Engineering
Background:
- Antibody fragments (Fabs) comprise variable (V) and constant (C) regions, with complementarity-determining regions (CDRs) forming the antigen-binding site (paratope).
- Paratope shape is influenced by CDR loops, elbow angle, and interdomain orientations, making their dynamics critical for antigen specificity.
Purpose of the Study:
- To investigate how affinity maturation, antibody humanization, and light-chain types affect the interface and elbow angle dynamics of Fabs.
- To understand the relationship between these dynamics and antigen specificity, affinity, and stability.
Main Methods:
- Studied nine antigen-binding fragments (Fabs) using computational methods to analyze interface and elbow angle dynamics.
- Examined conformational transitions on micro- to millisecond and nanosecond timescales.
Main Results:
- Affinity maturation led to significant rigidification of V-V interdomain and elbow-angle flexibility.
- Antibody humanization caused substantial shifts in V-V interdomain distributions, indicating framework-dependent orientation preferences.
- Fabs with different light chains exhibited high variability and flexibility in interface and elbow angle dynamics, with interconversion on the nanosecond timescale.
Conclusions:
- Fab interface orientations and elbow angles are dynamic and interconvert on the low nanosecond timescale.
- Understanding these dynamics is crucial for antibody modeling and engineering, impacting antigen specificity, affinity, and stability.
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