Retrieving functional pathways of biomolecules from single-particle snapshots

Ali Dashti, Ghoncheh Mashayekhi, Mrinal Shekhar, Danya Ben Hail, Salah Salah, Peter Schwander, Amedee des Georges (), Abhishek Singharoy (), Joachim Frank () and Abbas Ourmazd ()
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Ali Dashti: University of Wisconsin Milwaukee
Ghoncheh Mashayekhi: University of Wisconsin Milwaukee
Mrinal Shekhar: University of Illinois at Urbana-Champaign 405 N. Mathews Ave.
Danya Ben Hail: City University of New York
Salah Salah: City University of New York
Peter Schwander: University of Wisconsin Milwaukee
Amedee des Georges: City University of New York
Abhishek Singharoy: Arizona State University
Joachim Frank: Columbia University
Abbas Ourmazd: University of Wisconsin Milwaukee

Nature Communications, 2020, vol. 11, issue 1, 1-14

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.

Date: 2020
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DOI: 10.1038/s41467-020-18403-x

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