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  A Bayesian approach to extracting free-energy profiles from cryo-electron microscopy experiments

Giraldo-Barreto, J., Ortiz, S., Thiede, E. H., Palacio-Rodriguez, K., Carpenter, B., Barnett, A. H., et al. (2021). A Bayesian approach to extracting free-energy profiles from cryo-electron microscopy experiments. Scientific Reports, 11(1): 13657. doi:10.1038/s41598-021-92621-1.

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 Creators:
Giraldo-Barreto, Julian1, 2, Author
Ortiz, Sebastian1, Author
Thiede, Erik H.3, Author
Palacio-Rodriguez, Karen4, Author
Carpenter, Bob3, Author
Barnett, Alex H.3, Author
Cossio, Pilar1, 5, Author           
Affiliations:
1Biophysics of Tropical Diseases, Max Planck Tandem Group, University of Antioquia UdeA, Medellin, Colombia, ou_persistent22              
2Magnetism and Simulation Group, University of Antioquia UdeA, Medellín, Colombia, ou_persistent22              
3Center for Computational Mathematics, Flatiron Institute, New York City, USA, ou_persistent22              
4Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, Sorbonne Université, Paris, France, ou_persistent22              
5Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society, ou_2068292              

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 Abstract: Cryo-electron microscopy (cryo-EM) extracts single-particle density projections of individual biomolecules. Although cryo-EM is widely used for 3D reconstruction, due to its single-particle nature it has the potential to provide information about a biomolecule's conformational variability and underlying free-energy landscape. However, treating cryo-EM as a single-molecule technique is challenging because of the low signal-to-noise ratio (SNR) in individual particles. In this work, we propose the cryo-BIFE method (cryo-EM Bayesian Inference of Free-Energy profiles), which uses a path collective variable to extract free-energy profiles and their uncertainties from cryo-EM images. We test the framework on several synthetic systems where the imaging parameters and conditions were controlled. We found that for realistic cryo-EM environments and relevant biomolecular systems, it is possible to recover the underlying free energy, with the pose accuracy and SNR as crucial determinants. We then use the method to study the conformational transitions of a calcium-activated channel with real cryo-EM particles. Interestingly, we recover not only the most probable conformation (used to generate a high-resolution reconstruction of the calcium-bound state) but also a metastable state that corresponds to the calcium-unbound conformation. As expected for turnover transitions within the same sample, the activation barriers are on the order of [Formula: see text]. We expect our tool for extracting free-energy profiles from cryo-EM images to enable more complete characterization of the thermodynamic ensemble of biomolecules.

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Language(s): eng - English
 Dates: 2021-02-042021-06-012021-07-01
 Publication Status: Published online
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41598-021-92621-1
BibTex Citekey: giraldo-barreto_bayesian_2021
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Title: Scientific Reports
  Abbreviation : Sci. Rep.
Source Genre: Journal
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Publ. Info: London, UK : Nature Publishing Group
Pages: - Volume / Issue: 11 (1) Sequence Number: 13657 Start / End Page: - Identifier: ISSN: 2045-2322
CoNE: https://pure.mpg.de/cone/journals/resource/2045-2322