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 2\AA C$\alpha$ 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.
%0 Journal Article
%1 Del_Alamo2021-yt
%A Del Alamo, Diego
%A Jagessar, Kevin L
%A Meiler, Jens
%A Mchaourab, Hassane S
%D 2021
%I Public Library of Science (PLoS)
%J PLoS Comput. Biol.
%K topic_lifescience
%N 6
%P e1009107
%T Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints
%V 17
%X 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 2\AA C$\alpha$ 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.
@article{Del_Alamo2021-yt,
abstract = {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 2{\AA} C$\alpha$ 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.},
added-at = {2024-09-10T11:56:37.000+0200},
author = {Del Alamo, Diego and Jagessar, Kevin L and Meiler, Jens and Mchaourab, Hassane S},
biburl = {https://puma.scadsai.uni-leipzig.de/bibtex/24a09ef220ef10aa5dcd9604ac75f8aea/scadsfct},
copyright = {http://creativecommons.org/licenses/by/4.0/},
interhash = {60717663cb90cb6ca9aef3ff5093f3de},
intrahash = {4a09ef220ef10aa5dcd9604ac75f8aea},
journal = {PLoS Comput. Biol.},
keywords = {topic_lifescience},
language = {en},
month = jun,
number = 6,
pages = {e1009107},
publisher = {Public Library of Science (PLoS)},
timestamp = {2024-09-10T14:02:01.000+0200},
title = {Methodology for rigorous modeling of protein conformational changes by Rosetta using {DEER} distance restraints},
volume = 17,
year = 2021
}
