Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-18403-x
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Funding
- US Department of Energy, Office of Science, Basic Energy Sciences [DE-SC0002164]
- US National Science Foundation [STC 1231306, 1551489]
- UWM Research Growth Initiative
- HHMI [NIH GM55440, NIH GM29169]
- NIH [R35GM133598]
- CUNY
- NSF-MCB [1942763]
- Office of Science, US Department of Energy [DE-AC05-00OR22725]
- [NIH/R01GM095583]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1942763] Funding Source: National Science Foundation
- Division of Computing and Communication Foundations
- Direct For Computer & Info Scie & Enginr [1551489] Funding Source: National Science Foundation
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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. There is a great interest in retrieving functional pathways from cryo-EM single-particle data. Here, the authors present an approach that combines cryo-EM with advanced data-analytical methods and molecular dynamics simulations to reveal the functional pathways traversed on experimentally derived energy landscapes using the ryanodine receptor type 1 as an example.
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