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Higher Affinity Antibodies Bind With Lower Hydration and Flexibility in Large Scale Simulations.
Mabel T Y Wong1, Sebastian Kelm2, Xiaofeng Liu3
1School of Chemistry, University of Southampton, Southampton, United Kingdom.
Frontiers in Immunology
|June 16, 2022
Summary
Bridging water molecules and limited CDR flexibility at antibody-antigen interfaces correlate with higher antibody affinity, suggesting explicit hydration and flexibility are key for computational antibody design.
Area of Science:
- Biophysics
- Computational Chemistry
- Immunology
Background:
- Antibody-antigen interactions are crucial for therapeutic applications.
- Understanding interface dynamics and hydration is essential for predicting binding affinity.
Purpose of the Study:
- To investigate the role of interface conformation and hydration in antibody-antigen binding.
- To explore the impact of explicit water and protein flexibility on binding affinity.
Main Methods:
- Long-timescale molecular dynamics simulations with enhanced sampling.
- Replica exchange simulations of nine antibody-antigen pairs in bound and unbound states.
- Analysis of interface water molecules and complementarity-determining region (CDR) conformational sampling.
Main Results:
- Identified significant bridging water molecules at the antibody-antigen interface.
- Observed a correlation between higher antibody affinity, reduced bulk water interactions, and lower CDR conformational sampling when antigen is bound.
- Found that CDR sampling differences do not correlate with affinity, supporting enthalpic binding.
Conclusions:
- Interface hydration and CDR conformational flexibility are critical factors modulating antibody-antigen binding affinity.
- Explicit hydration and CDR flexibility should be incorporated into computational workflows for improved antibody affinity prediction and design.
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