og:image: 
citation_mjid: pnas;1816909116v1
article:published_time: 2019-03-19
og:site_name: PNAS
citation_reference: citation_journal_title=PNAS;citation_journal_abbrev=Proc. Natl. Acad. Sci. USA;citation_author=DE. Koshland;citation_title=Application of a Theory of Enzyme Specificity to Protein Synthesis;citation_pages=98-104;citation_volume=44;citation_year=1958;citation_issue=2;citation_pmid=16590179;citation_doi=10.1073/pnas.44.2.98
citation_journal_title: Proceedings of the National Academy of Sciences
type: article
og:description: Protein?ligand interactions are commonly described in terms of a two-state or a lock-and-key mechanism. To provide a more detailed and dynamic description of receptor?ligand bonds and their (un)binding path, we combined high-speed force spectroscopy and molecular dynamics simulations to probe the prototypical streptavidin?biotin complex. The excellent agreement observed, never used for force-field refinement, provides the most direct test of the ?computational microscope.? The so-far largest dynamic range of loading rates explored (11 decades) enabled accurate reconstruction of the free-energy landscape. We revealed velocity-dependent unbinding pathways and intermediate states that enhance rebinding, explaining the long lifetime of the bond. We expect similar behavior in most receptor?ligand complexes, implying unbinding pathways governed by transient, timescale-dependent induced fits.  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 on the full unbinding pathway is often 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, replacing a simple two-state picture with one that involves many routes to the lock and rate-dependent induced-fit motions for intermediates, which might be relevant for other receptor?ligand bonds.
citation_author_email: felix.rico@inserm.fr
citation_issn: 0027-8424
citation_full_html_url: https://www.pnas.org/content/early/2019/03/18/1816909116.full
citation_public_url: https://www.pnas.org/content/early/2019/03/18/1816909116
dc:title: Heterogeneous and rate-dependent streptavidin?biotin unbinding revealed by high-speed force spectroscopy and atomistic simulations | PNAS
Content-Encoding: UTF-8
citation_pdf_url: https://www.pnas.org/content/pnas/early/2019/03/18/1816909116.full.pdf
citation_section: PNAS Plus
citation_num_pages: 8
citation_fulltext_world_readable: 
citation_journal_abbrev: PNAS
DC.Identifier: 10.1073/pnas.1816909116
DC.Rights: Copyright © 2019 the Author(s). Published by PNAS.. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
citation_author: Felix Rico
citation_abstract_html_url: https://www.pnas.org/content/early/2019/03/18/1816909116.abstract
HW.identifier: /pnas/early/2019/03/18/1816909116.atom
citation_doi: 10.1073/pnas.1816909116
Content-Language: en
format-detection: telephone=no
Generator: Drupal 7 (http://drupal.org)
citation_author_orcid: http://orcid.org/0000-0002-7757-8340
DC.AccessRights: open-access
citation_publication_date: 2019/03/19
citation_title: Heterogeneous and rate-dependent streptavidin?biotin unbinding revealed by high-speed force spectroscopy and atomistic simulations
citation_author_institution: Aix-Marseille Université
citation_publisher: National Academy of Sciences
citation_id: 1816909116v1
title: Heterogeneous and rate-dependent streptavidin?biotin unbinding revealed by high-speed force spectroscopy and atomistic simulations | PNAS
DC.Description: Protein?ligand interactions are commonly described in terms of a two-state or a lock-and-key mechanism. To provide a more detailed and dynamic description of receptor?ligand bonds and their (un)binding path, we combined high-speed force spectroscopy and molecular dynamics simulations to probe the prototypical streptavidin?biotin complex. The excellent agreement observed, never used for force-field refinement, provides the most direct test of the ?computational microscope.? The so-far largest dynamic range of loading rates explored (11 decades) enabled accurate reconstruction of the free-energy landscape. We revealed velocity-dependent unbinding pathways and intermediate states that enhance rebinding, explaining the long lifetime of the bond. We expect similar behavior in most receptor?ligand complexes, implying unbinding pathways governed by transient, timescale-dependent induced fits.  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 on the full unbinding pathway is often 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, replacing a simple two-state picture with one that involves many routes to the lock and rate-dependent induced-fit motions for intermediates, which might be relevant for other receptor?ligand bonds.
Content-Type-Hint: text/html; charset=utf-8
DC.Format: text/html
DC.Publisher: National Academy of Sciences
DC.Contributor: Felix Rico
Content-Type: application/xhtml+xml; charset=UTF-8
X-Parsed-By: org.apache.tika.parser.DefaultParser
og:type: article
article:section: PNAS Plus
citation_pmid: 30890636
citation_article_type: Research Article
og:title: Heterogeneous and rate-dependent streptavidin?biotin unbinding revealed by high-speed force spectroscopy and atomistic simulations
citation_abstract: <p>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 on the full unbinding pathway is often 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, replacing a simple two-state picture with one that involves many routes to the lock and rate-dependent induced-fit motions for intermediates, which might be relevant for other receptor?ligand bonds.</p>
DC.Title: Heterogeneous and rate-dependent streptavidin?biotin unbinding revealed by high-speed force spectroscopy and atomistic simulations
citation_firstpage: 201816909
viewport: initial-scale=1, maximum-scale=1, width=device-width, user-scalable=yes
citation_funding_source: citation_funder_id=501100001665;citation_grant_number=ANR-15-CE11- 0007 (BioHSFS);
HW.pisa: pnas;1816909116v1
DC.Language: en
DC.Date: 2019-03-19
citation_access: all
category: research-article
og:url: https://www.pnas.org/content/early/2019/03/18/1816909116