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

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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-AA3C-C Version Permalink: http://hdl.handle.net/21.11116/0000-0003-70CE-7
Genre: Journal Article

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Rico, F., Author
Russek, A.1, Author              
Gonzalez, L., Author
Grubmüller, H.1, Author              
Scheuring, S., Author
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1Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society, ou_578631              

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 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.

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Language(s): eng - English
 Dates: 2019-04-02
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1073/pnas.1816909116
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Title: Proceedings of the National Academy of Sciences of the United States of America
Source Genre: Journal
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Pages: - Volume / Issue: 116 (14) Sequence Number: - Start / End Page: 6594 - 6601 Identifier: -