Molecular dynamics force probe simulations of antibody/antigen unbinding: 
Entropic control and non-additivity of unbinding forces.

Heymann, B.; Grubmueller, H.

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Molecular dynamics force probe simulations of antibody/antigen unbinding: Entropic control and non-additivity of unbinding forces.

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Heymann, B.
Research Group of Theoretical Molecular Biophysics, MPI for biophysical chemistry, Max Planck Society;

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Grubmueller, H.
Research Group of Theoretical Molecular Biophysics, MPI for biophysical chemistry, Max Planck Society;

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Citation

Heymann, B., & Grubmueller, H. (2001). Molecular dynamics force probe simulations of antibody/antigen unbinding: Entropic control and non-additivity of unbinding forces. Biophysical Journal, 81(3), 1295-1313.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0012-F63B-0

Abstract

Unbinding of a spin-labeled dinitrophenyl (DNP) hapten from the monoclonal antibody AN02 Fab fragment has been studied by force probe molecular dynamics (FPMD) simulations. In our nanosecond simulations, unbinding was enforced by pulling the hapten molecule out of the binding pocket. Detailed inspection of the FPMD trajectories revealed a large heterogeneity of enforced unbinding pathways and a correspondingly large flexibility of the binding pocket region, which exhibited induced fit motions. Principal component analyses were used to estimate the resulting entropic contribution of ∼6 kcal/mol to the AN02/DNP-hapten bond. This large contribution may explain the surprisingly large effect on binding kinetics found for mutation sites that are not directly involved in binding. We propose that such “entropic control” optimizes the binding kinetics of antibodies. Additional FPMD simulations of two point mutants in the light chain, Y33F and I96K, provided further support for a large flexibility of the binding pocket. Unbinding forces were found to be unchanged for these two mutants. Structural analysis of the FPMD simulations suggests that, in contrast to free energies of unbinding, the effect of mutations on unbinding forces is generally nonadditive.