Molecular evolution of affinity and flexibility in the immune system
Ian F Thorpe1, Charles L Brooks
1Center for Theoretical Biological Physics and Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Summary
Antibody maturation involves evolving higher affinity for antigens. This study reveals that increased antibody affinity correlates with reduced protein flexibility, a key factor in molecular evolution.
Area of Science:
- Immunology
- Molecular Biology
- Biophysics
Background:
- Antibodies mature to increase antigen affinity during immune responses.
- Understanding molecular factors controlling antibody maturation is crucial.
Purpose of the Study:
- Investigate molecular changes in antibody flexibility during maturation.
- Correlate flexibility changes with ligand binding affinity.
Main Methods:
- Molecular dynamics simulations were used.
- Analyzed flexibility of the 4-4-20 antibody at four maturation stages.
- Computed binding free energies for antibody-ligand complexes.
Main Results:
- Increased antibody affinity is linked to decreased entropic cost of binding.
- Computed binding free energies qualitatively matched experimental trends.
- A correlation between high-affinity binding and reduced protein flexibility was observed.
Conclusions:
- Decreased protein flexibility is associated with high-affinity antibody-ligand interactions.
- This flexibility-affinity relationship is likely a general principle in molecular association.
- This finding is key to understanding antibody evolution in immune responses.
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