Cargando…
The Effect of Tensile Stress on the Conformational Free Energy Landscape of Disulfide Bonds
Disulfide bridges are no longer considered to merely stabilize protein structure, but are increasingly recognized to play a functional role in many regulatory biomolecular processes. Recent studies have uncovered that the redox activity of native disulfides depends on their C–C–S–S dihedrals, [Image...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186883/ https://www.ncbi.nlm.nih.gov/pubmed/25286308 http://dx.doi.org/10.1371/journal.pone.0108812 |
_version_ | 1782338131590119424 |
---|---|
author | Anjukandi, Padmesh Dopieralski, Przemyslaw Ribas–Arino, Jordi Marx, Dominik |
author_facet | Anjukandi, Padmesh Dopieralski, Przemyslaw Ribas–Arino, Jordi Marx, Dominik |
author_sort | Anjukandi, Padmesh |
collection | PubMed |
description | Disulfide bridges are no longer considered to merely stabilize protein structure, but are increasingly recognized to play a functional role in many regulatory biomolecular processes. Recent studies have uncovered that the redox activity of native disulfides depends on their C–C–S–S dihedrals, [Image: see text] and [Image: see text]. Moreover, the interplay of chemical reactivity and mechanical stress of disulfide switches has been recently elucidated using force–clamp spectroscopy and computer simulation. The [Image: see text] and [Image: see text] angles have been found to change from conformations that are open to nucleophilic attack to sterically hindered, so–called closed states upon exerting tensile stress. In view of the growing evidence of the importance of C–C–S–S dihedrals in tuning the reactivity of disulfides, here we present a systematic study of the conformational diversity of disulfides as a function of tensile stress. With the help of force-clamp metadynamics simulations, we show that tensile stress brings about a large stabilization of the closed conformers, thereby giving rise to drastic changes in the conformational free energy landscape of disulfides. Statistical analysis shows that native TDi, DO and interchain Ig protein disulfides prefer open conformations, whereas the intrachain disulfide bridges in Ig proteins favor closed conformations. Correlating mechanical stress with the distance between the two [Image: see text]–carbons of the disulfide moiety reveals that the strain of intrachain Ig protein disulfides corresponds to a mechanical activation of about 100 pN. Such mechanical activation leads to a severalfold increase of the rate of the elementary redox [Image: see text] reaction step. All these findings constitute a step forward towards achieving a full understanding of functional disulfides. |
format | Online Article Text |
id | pubmed-4186883 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41868832014-10-16 The Effect of Tensile Stress on the Conformational Free Energy Landscape of Disulfide Bonds Anjukandi, Padmesh Dopieralski, Przemyslaw Ribas–Arino, Jordi Marx, Dominik PLoS One Research Article Disulfide bridges are no longer considered to merely stabilize protein structure, but are increasingly recognized to play a functional role in many regulatory biomolecular processes. Recent studies have uncovered that the redox activity of native disulfides depends on their C–C–S–S dihedrals, [Image: see text] and [Image: see text]. Moreover, the interplay of chemical reactivity and mechanical stress of disulfide switches has been recently elucidated using force–clamp spectroscopy and computer simulation. The [Image: see text] and [Image: see text] angles have been found to change from conformations that are open to nucleophilic attack to sterically hindered, so–called closed states upon exerting tensile stress. In view of the growing evidence of the importance of C–C–S–S dihedrals in tuning the reactivity of disulfides, here we present a systematic study of the conformational diversity of disulfides as a function of tensile stress. With the help of force-clamp metadynamics simulations, we show that tensile stress brings about a large stabilization of the closed conformers, thereby giving rise to drastic changes in the conformational free energy landscape of disulfides. Statistical analysis shows that native TDi, DO and interchain Ig protein disulfides prefer open conformations, whereas the intrachain disulfide bridges in Ig proteins favor closed conformations. Correlating mechanical stress with the distance between the two [Image: see text]–carbons of the disulfide moiety reveals that the strain of intrachain Ig protein disulfides corresponds to a mechanical activation of about 100 pN. Such mechanical activation leads to a severalfold increase of the rate of the elementary redox [Image: see text] reaction step. All these findings constitute a step forward towards achieving a full understanding of functional disulfides. Public Library of Science 2014-10-06 /pmc/articles/PMC4186883/ /pubmed/25286308 http://dx.doi.org/10.1371/journal.pone.0108812 Text en © 2014 Anjukandi et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Anjukandi, Padmesh Dopieralski, Przemyslaw Ribas–Arino, Jordi Marx, Dominik The Effect of Tensile Stress on the Conformational Free Energy Landscape of Disulfide Bonds |
title | The Effect of Tensile Stress on the Conformational Free Energy Landscape of Disulfide Bonds |
title_full | The Effect of Tensile Stress on the Conformational Free Energy Landscape of Disulfide Bonds |
title_fullStr | The Effect of Tensile Stress on the Conformational Free Energy Landscape of Disulfide Bonds |
title_full_unstemmed | The Effect of Tensile Stress on the Conformational Free Energy Landscape of Disulfide Bonds |
title_short | The Effect of Tensile Stress on the Conformational Free Energy Landscape of Disulfide Bonds |
title_sort | effect of tensile stress on the conformational free energy landscape of disulfide bonds |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186883/ https://www.ncbi.nlm.nih.gov/pubmed/25286308 http://dx.doi.org/10.1371/journal.pone.0108812 |
work_keys_str_mv | AT anjukandipadmesh theeffectoftensilestressontheconformationalfreeenergylandscapeofdisulfidebonds AT dopieralskiprzemyslaw theeffectoftensilestressontheconformationalfreeenergylandscapeofdisulfidebonds AT ribasarinojordi theeffectoftensilestressontheconformationalfreeenergylandscapeofdisulfidebonds AT marxdominik theeffectoftensilestressontheconformationalfreeenergylandscapeofdisulfidebonds AT anjukandipadmesh effectoftensilestressontheconformationalfreeenergylandscapeofdisulfidebonds AT dopieralskiprzemyslaw effectoftensilestressontheconformationalfreeenergylandscapeofdisulfidebonds AT ribasarinojordi effectoftensilestressontheconformationalfreeenergylandscapeofdisulfidebonds AT marxdominik effectoftensilestressontheconformationalfreeenergylandscapeofdisulfidebonds |