Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase

Abstract The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme. As a result of disulfide shuffling in its terminal domains, hPDI exists in two oxidation states with different conformational preferences which are important for substrate binding and functiona...

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Autores principales:	Razieh Karamzadeh, Mohammad Hossein Karimi-Jafari, Ali Sharifi-Zarchi, Hamidreza Chitsaz, Ghasem Hosseini Salekdeh, Ali Akbar Moosavi-Movahedi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d0419dec1dcd4d559403cd172a5bb667
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spelling	oai:doaj.org-article:d0419dec1dcd4d559403cd172a5bb6672021-12-02T16:07:00ZMachine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase10.1038/s41598-017-03966-52045-2322https://doaj.org/article/d0419dec1dcd4d559403cd172a5bb6672017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03966-5https://doaj.org/toc/2045-2322Abstract The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme. As a result of disulfide shuffling in its terminal domains, hPDI exists in two oxidation states with different conformational preferences which are important for substrate binding and functional activities. Here, we address the redox-dependent conformational dynamics of hPDI through molecular dynamics (MD) simulations. Collective domain motions are identified by the principal component analysis of MD trajectories and redox-dependent opening-closing structure variations are highlighted on projected free energy landscapes. Then, important structural features that exhibit considerable differences in dynamics of redox states are extracted by statistical machine learning methods. Mapping the structural variations to time series of residue interaction networks also provides a holistic representation of the dynamical redox differences. With emphasizing on persistent long-lasting interactions, an approach is proposed that compiled these time series networks to a single dynamic residue interaction network (DRIN). Differential comparison of DRIN in oxidized and reduced states reveals chains of residue interactions that represent potential allosteric paths between catalytic and ligand binding sites of hPDI.Razieh KaramzadehMohammad Hossein Karimi-JafariAli Sharifi-ZarchiHamidreza ChitsazGhasem Hosseini SalekdehAli Akbar Moosavi-MovahediNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Razieh Karamzadeh Mohammad Hossein Karimi-Jafari Ali Sharifi-Zarchi Hamidreza Chitsaz Ghasem Hosseini Salekdeh Ali Akbar Moosavi-Movahedi Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase
description	Abstract The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme. As a result of disulfide shuffling in its terminal domains, hPDI exists in two oxidation states with different conformational preferences which are important for substrate binding and functional activities. Here, we address the redox-dependent conformational dynamics of hPDI through molecular dynamics (MD) simulations. Collective domain motions are identified by the principal component analysis of MD trajectories and redox-dependent opening-closing structure variations are highlighted on projected free energy landscapes. Then, important structural features that exhibit considerable differences in dynamics of redox states are extracted by statistical machine learning methods. Mapping the structural variations to time series of residue interaction networks also provides a holistic representation of the dynamical redox differences. With emphasizing on persistent long-lasting interactions, an approach is proposed that compiled these time series networks to a single dynamic residue interaction network (DRIN). Differential comparison of DRIN in oxidized and reduced states reveals chains of residue interactions that represent potential allosteric paths between catalytic and ligand binding sites of hPDI.
format	article
author	Razieh Karamzadeh Mohammad Hossein Karimi-Jafari Ali Sharifi-Zarchi Hamidreza Chitsaz Ghasem Hosseini Salekdeh Ali Akbar Moosavi-Movahedi
author_facet	Razieh Karamzadeh Mohammad Hossein Karimi-Jafari Ali Sharifi-Zarchi Hamidreza Chitsaz Ghasem Hosseini Salekdeh Ali Akbar Moosavi-Movahedi
author_sort	Razieh Karamzadeh
title	Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase
title_short	Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase
title_full	Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase
title_fullStr	Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase
title_full_unstemmed	Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase
title_sort	machine learning and network analysis of molecular dynamics trajectories reveal two chains of red/ox-specific residue interactions in human protein disulfide isomerase
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d0419dec1dcd4d559403cd172a5bb667
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Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase

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