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Title: Retrieving functional pathways of biomolecules from single-particle snapshots

Abstract

Abstract A primary reason for the intense interest in structural biology is the fact that knowledge of structure can elucidate macromolecular functions in living organisms. Sustained effort has resulted in an impressive arsenal of tools for determining the static structures. But under physiological conditions, macromolecules undergo continuous conformational changes, a subset of which are functionally important. Techniques for capturing the continuous conformational changes underlying function are essential for further progress. Here, we present chemically-detailed conformational movies of biological function, extracted data-analytically from experimental single-particle cryo-electron microscopy (cryo-EM) snapshots of ryanodine receptor type 1 (RyR1), a calcium-activated calcium channel engaged in the binding of ligands. The functional motions differ substantially from those inferred from static structures in the nature of conformationally active structural domains, the sequence and extent of conformational motions, and the way allosteric signals are transduced within and between domains. Our approach highlights the importance of combining experiment, advanced data analysis, and molecular simulations.

Authors:
; ; ORCiD logo; ; ; ORCiD logo; ORCiD logo; ORCiD logo; ORCiD logo; ORCiD logo
Publication Date:
Research Org.:
Univ. of Wisconsin, Milwaukee, WI (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF); National Institutes of Health (NIH)
OSTI Identifier:
1664467
Alternate Identifier(s):
OSTI ID: 1712430
Grant/Contract Number:  
SC0002164; STC 1231306; STC 1551489; NIH GM55440; NIH GM29169; R35GM133598; MCB194276; R01GM095583; AC05-00OR22725
Resource Type:
Published Article
Journal Name:
Nature Communications
Additional Journal Information:
Journal Name: Nature Communications Journal Volume: 11 Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United Kingdom
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Computational biophysics; computational models

Citation Formats

Dashti, Ali, Mashayekhi, Ghoncheh, Shekhar, Mrinal, Ben Hail, Danya, Salah, Salah, Schwander, Peter, des Georges, Amedee, Singharoy, Abhishek, Frank, Joachim, and Ourmazd, Abbas. Retrieving functional pathways of biomolecules from single-particle snapshots. United Kingdom: N. p., 2020. Web. https://doi.org/10.1038/s41467-020-18403-x.
Dashti, Ali, Mashayekhi, Ghoncheh, Shekhar, Mrinal, Ben Hail, Danya, Salah, Salah, Schwander, Peter, des Georges, Amedee, Singharoy, Abhishek, Frank, Joachim, & Ourmazd, Abbas. Retrieving functional pathways of biomolecules from single-particle snapshots. United Kingdom. https://doi.org/10.1038/s41467-020-18403-x
Dashti, Ali, Mashayekhi, Ghoncheh, Shekhar, Mrinal, Ben Hail, Danya, Salah, Salah, Schwander, Peter, des Georges, Amedee, Singharoy, Abhishek, Frank, Joachim, and Ourmazd, Abbas. Fri . "Retrieving functional pathways of biomolecules from single-particle snapshots". United Kingdom. https://doi.org/10.1038/s41467-020-18403-x.
@article{osti_1664467,
title = {Retrieving functional pathways of biomolecules from single-particle snapshots},
author = {Dashti, Ali and Mashayekhi, Ghoncheh and Shekhar, Mrinal and Ben Hail, Danya and Salah, Salah and Schwander, Peter and des Georges, Amedee and Singharoy, Abhishek and Frank, Joachim and Ourmazd, Abbas},
abstractNote = {Abstract A primary reason for the intense interest in structural biology is the fact that knowledge of structure can elucidate macromolecular functions in living organisms. Sustained effort has resulted in an impressive arsenal of tools for determining the static structures. But under physiological conditions, macromolecules undergo continuous conformational changes, a subset of which are functionally important. Techniques for capturing the continuous conformational changes underlying function are essential for further progress. Here, we present chemically-detailed conformational movies of biological function, extracted data-analytically from experimental single-particle cryo-electron microscopy (cryo-EM) snapshots of ryanodine receptor type 1 (RyR1), a calcium-activated calcium channel engaged in the binding of ligands. The functional motions differ substantially from those inferred from static structures in the nature of conformationally active structural domains, the sequence and extent of conformational motions, and the way allosteric signals are transduced within and between domains. Our approach highlights the importance of combining experiment, advanced data analysis, and molecular simulations.},
doi = {10.1038/s41467-020-18403-x},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United Kingdom},
year = {2020},
month = {9}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1038/s41467-020-18403-x

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