Conformational preludes to the latency transition in PAI-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry

Abstract Both function and dysfunction of serine protease inhibitors (serpins) involve massive conformational change in their tertiary structure but the dynamics facilitating these events remain poorly understood. We have studied the dynamic preludes to conformational change in the serpin plasminoge...

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Autores principales:	Michael Petersen, Jeppe B. Madsen, Thomas J. D. Jørgensen, Morten B. Trelle
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2be4f4e67be6467ca11b18fe2c3a033a
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spelling	oai:doaj.org-article:2be4f4e67be6467ca11b18fe2c3a033a2021-12-02T15:05:00ZConformational preludes to the latency transition in PAI-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry10.1038/s41598-017-06290-02045-2322https://doaj.org/article/2be4f4e67be6467ca11b18fe2c3a033a2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06290-0https://doaj.org/toc/2045-2322Abstract Both function and dysfunction of serine protease inhibitors (serpins) involve massive conformational change in their tertiary structure but the dynamics facilitating these events remain poorly understood. We have studied the dynamic preludes to conformational change in the serpin plasminogen activator inhibitor 1 (PAI-1). We report the first multi-microsecond atomistic molecular dynamics simulations of PAI-1 and compare the data with experimental hydrogen/deuterium-exchange data (HDXMS). The simulations reveal notable conformational flexibility of helices D, E and F and major fluctuations are observed in the W86-loop which occasionally leads to progressive detachment of β-strand 2 A from β-strand 3 A. An interesting correlation between Cα-RMSD values from simulations and experimental HDXMS data is observed. Helices D, E and F are known to be important for the overall stability of active PAI-1 as ligand binding in this region can accelerate or decelerate the conformational inactivation. Plasticity in this region may thus be mechanistically linked to the conformational change, possibly through facilitation of further unfolding of the hydrophobic core, as previously reported. This study provides a promising example of how computer simulations can help tether out mechanisms of serpin function and dysfunction at a spatial and temporal resolution that is far beyond the reach of any experiment.Michael PetersenJeppe B. MadsenThomas J. D. JørgensenMorten B. TrelleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michael Petersen Jeppe B. Madsen Thomas J. D. Jørgensen Morten B. Trelle Conformational preludes to the latency transition in PAI-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry
description	Abstract Both function and dysfunction of serine protease inhibitors (serpins) involve massive conformational change in their tertiary structure but the dynamics facilitating these events remain poorly understood. We have studied the dynamic preludes to conformational change in the serpin plasminogen activator inhibitor 1 (PAI-1). We report the first multi-microsecond atomistic molecular dynamics simulations of PAI-1 and compare the data with experimental hydrogen/deuterium-exchange data (HDXMS). The simulations reveal notable conformational flexibility of helices D, E and F and major fluctuations are observed in the W86-loop which occasionally leads to progressive detachment of β-strand 2 A from β-strand 3 A. An interesting correlation between Cα-RMSD values from simulations and experimental HDXMS data is observed. Helices D, E and F are known to be important for the overall stability of active PAI-1 as ligand binding in this region can accelerate or decelerate the conformational inactivation. Plasticity in this region may thus be mechanistically linked to the conformational change, possibly through facilitation of further unfolding of the hydrophobic core, as previously reported. This study provides a promising example of how computer simulations can help tether out mechanisms of serpin function and dysfunction at a spatial and temporal resolution that is far beyond the reach of any experiment.
format	article
author	Michael Petersen Jeppe B. Madsen Thomas J. D. Jørgensen Morten B. Trelle
author_facet	Michael Petersen Jeppe B. Madsen Thomas J. D. Jørgensen Morten B. Trelle
author_sort	Michael Petersen
title	Conformational preludes to the latency transition in PAI-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry
title_short	Conformational preludes to the latency transition in PAI-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry
title_full	Conformational preludes to the latency transition in PAI-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry
title_fullStr	Conformational preludes to the latency transition in PAI-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry
title_full_unstemmed	Conformational preludes to the latency transition in PAI-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry
title_sort	conformational preludes to the latency transition in pai-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2be4f4e67be6467ca11b18fe2c3a033a
work_keys_str_mv	AT michaelpetersen conformationalpreludestothelatencytransitioninpai1asdeterminedbyatomisticcomputersimulationsandhydrogendeuteriumexchangemassspectrometry AT jeppebmadsen conformationalpreludestothelatencytransitioninpai1asdeterminedbyatomisticcomputersimulationsandhydrogendeuteriumexchangemassspectrometry AT thomasjdjørgensen conformationalpreludestothelatencytransitioninpai1asdeterminedbyatomisticcomputersimulationsandhydrogendeuteriumexchangemassspectrometry AT mortenbtrelle conformationalpreludestothelatencytransitioninpai1asdeterminedbyatomisticcomputersimulationsandhydrogendeuteriumexchangemassspectrometry
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Conformational preludes to the latency transition in PAI-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry

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