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Heterogeneous and rate-dependent streptavidin-biotin unbinding revealed by high-speed force spectroscopy and molecular dynamics simulations

MPS-Authors
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Russek,  A.
Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society;

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Grubmüller,  H.
Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society;

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3014617.pdf
(Publisher version), 2MB

Supplementary Material (public)

3014617_Suppl.htm
(Supplementary material), 199KB

Citation

Rico, F., Russek, A., Gonzalez, L., Grubmüller, H., & Scheuring, S. (2019). Heterogeneous and rate-dependent streptavidin-biotin unbinding revealed by high-speed force spectroscopy and molecular dynamics simulations. Proceedings of the National Academy of Sciences of the United States of America, 116(14), 6594-6601. doi:10.1073/pnas.1816909116.


Cite as: http://hdl.handle.net/21.11116/0000-0002-AA3C-C
Abstract
Receptor-ligand interactions are essential for biological function and their binding strength is commonly explained in terms of static lock-and-key models based on molecular complementarity. However, detailed information of the full unbinding pathway is commonly lacking due, in part, to the static nature of atomic structures and ensemble averaging inherent to bulk biophysics approaches. Here we combine molecular dynamics and high-speed force spectroscopy on the streptavidin-biotin complex to determine the binding strength and unbinding pathways over the widest dynamic range. Experiment and simulation show excellent agreement at overlapping velocities and provided evidence of the unbinding mechanisms. During unbinding, biotin crosses multiple energy barriers and visits various intermediate states far from the binding pocket while streptavidin undergoes transient induced fits, all varying with loading rate. This multistate process slows down the transition to the unbound state and favors rebinding, thus explaining the long lifetime of the complex. We provide an atomistic, dynamic picture of the unbinding process, suggesting that the lock-and-key mechanism may need revision in terms of many routes to the lock that might be relevant for other receptor-ligand bonds.