Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints.

We describe an approach for integrating distance restraints from Double Electron-Electron Resonance (DEER) spectroscopy into Rosetta with the purpose of modeling alternative protein conformations from an initial experimental structure. Fundamental to this approach is a multilateration algorithm that...

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Autores principales:	Diego Del Alamo, Kevin L Jagessar, Jens Meiler, Hassane S Mchaourab
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1599e04c3312432790c834f98fa1720e
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id	oai:doaj.org-article:1599e04c3312432790c834f98fa1720e
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spelling	oai:doaj.org-article:1599e04c3312432790c834f98fa1720e2021-11-25T05:40:36ZMethodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints.1553-734X1553-735810.1371/journal.pcbi.1009107https://doaj.org/article/1599e04c3312432790c834f98fa1720e2021-06-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009107https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358We describe an approach for integrating distance restraints from Double Electron-Electron Resonance (DEER) spectroscopy into Rosetta with the purpose of modeling alternative protein conformations from an initial experimental structure. Fundamental to this approach is a multilateration algorithm that harnesses sets of interconnected spin label pairs to identify optimal rotamer ensembles at each residue that fit the DEER decay in the time domain. Benchmarked relative to data analysis packages, the algorithm yields comparable distance distributions with the advantage that fitting the DEER decay and rotamer ensemble optimization are coupled. We demonstrate this approach by modeling the protonation-dependent transition of the multidrug transporter PfMATE to an inward facing conformation with a deviation to the experimental structure of less than 2Å Cα RMSD. By decreasing spin label rotamer entropy, this approach engenders more accurate Rosetta models that are also more closely clustered, thus setting the stage for more robust modeling of protein conformational changes.Diego Del AlamoKevin L JagessarJens MeilerHassane S MchaourabPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 6, p e1009107 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Diego Del Alamo Kevin L Jagessar Jens Meiler Hassane S Mchaourab Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints.
description	We describe an approach for integrating distance restraints from Double Electron-Electron Resonance (DEER) spectroscopy into Rosetta with the purpose of modeling alternative protein conformations from an initial experimental structure. Fundamental to this approach is a multilateration algorithm that harnesses sets of interconnected spin label pairs to identify optimal rotamer ensembles at each residue that fit the DEER decay in the time domain. Benchmarked relative to data analysis packages, the algorithm yields comparable distance distributions with the advantage that fitting the DEER decay and rotamer ensemble optimization are coupled. We demonstrate this approach by modeling the protonation-dependent transition of the multidrug transporter PfMATE to an inward facing conformation with a deviation to the experimental structure of less than 2Å Cα RMSD. By decreasing spin label rotamer entropy, this approach engenders more accurate Rosetta models that are also more closely clustered, thus setting the stage for more robust modeling of protein conformational changes.
format	article
author	Diego Del Alamo Kevin L Jagessar Jens Meiler Hassane S Mchaourab
author_facet	Diego Del Alamo Kevin L Jagessar Jens Meiler Hassane S Mchaourab
author_sort	Diego Del Alamo
title	Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints.
title_short	Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints.
title_full	Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints.
title_fullStr	Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints.
title_full_unstemmed	Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints.
title_sort	methodology for rigorous modeling of protein conformational changes by rosetta using deer distance restraints.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/1599e04c3312432790c834f98fa1720e
work_keys_str_mv	AT diegodelalamo methodologyforrigorousmodelingofproteinconformationalchangesbyrosettausingdeerdistancerestraints AT kevinljagessar methodologyforrigorousmodelingofproteinconformationalchangesbyrosettausingdeerdistancerestraints AT jensmeiler methodologyforrigorousmodelingofproteinconformationalchangesbyrosettausingdeerdistancerestraints AT hassanesmchaourab methodologyforrigorousmodelingofproteinconformationalchangesbyrosettausingdeerdistancerestraints
_version_	1718414502208208896

Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints.

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