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Organizers: Joakim Andén, Dorit Hanein, Roy R. Lederman and Steven J. Ludtke
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Next Talk
Massimiliano Bonomi
CNRS Researcher
Institut Pasteur
Date and time: May 7th, 2025 Wednesday at 8am PST / 11am EST / 3pm GMT / 5pm CET / 11pm China
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Protein structural ensembles from 3D and 2D cryo-EM data
Understanding the molecular mechanisms employed by biological systems to carry out their functions is often essential for rationally targeting associated diseases. In many cases, determining the three- dimensional (3D) structure of these systems provides valuable insights. However, it is frequently the interplay between structural and dynamical properties that determines the behavior of complex systems. While both experimental and computational methods are invaluable tools for studying protein structure and dynamics, limitations in each individual technique can hinder their capabilities [1]. Here, I will present two integrative computational-experimental approaches to combine cryo-electron microscopy (cryo-EM) data (and more) into molecular dynamics (MD) simulations to determine accurate protein structural ensembles [2,3]. I will showcase the capabilities of these methods using different applications to biological systems of outstanding interest. First, I will illustrate how accurate protein structural ensembles can be obtained from 3D cryo-electron microscopy maps with our recently developed EMMIVox approach [4]. Then, I will focus on characterizing the structural and dynamic properties of the CyaA toxin by combining coarse-grained MD simulations with Hydrogen/Deuterium eXchange Mass Spectrometry (HDX-MS), Small Angle X-ray Scattering (SAXS), and 2D single-particle cryo-EM data. Finally, I will show how AlphaFold2 and single-particle cryo-EM images can be synergistically used to characterize the alternative, functional states of a G-Protein Coupled Receptor.
Last Talk
Sonya Hanson
Research Scientist
Flatiron Institute
Date and time: March 5th, 2025 Wednesday at 8am PST / 11am EST / 4pm GMT / 5pm CET / 12am China
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The Inaugural Flatiron Institute Cryo-EM Conformational Heterogeneity Challenge
Despite the rise of single particle cryo-EM as a premier method for resolving macromolecular structures at atomic resolution, methods to address molecular heterogeneity in vitrified samples have yet to reach maturity. With an increasing number of new methods to analyze the multitude of heterogeneous states captured in single particle images, a systemic approach to benchmarks and metrics in this field is needed. With this motivation, we issued a challenge to the community to analyze two curated cryo-EM image stacks of the thyroglobulin molecule with conformational heterogeneity: the first was a typical experimental dataset, and the second was synthetically generated, allowing control over the distribution of molecular structures in the particle images. This synthetic dataset also enabled direct comparison between participants’ submissions and the ground truth molecular structures and distributions. Participants were asked to submit 80 molecular volumes representing the heterogeneous ensemble in the dataset and estimate their respective populations in the particle stack provided. Participation in the challenge was strong, with submissions from nearly all developers of heterogeneity methods, resulting in 40 submissions across both datasets. Submissions qualitatively exceeded expectations, with the molecular motions identified by methods resembling both each other and the ground truth distribution. However, quantitatively assessing these similarities was a challenge in and of itself. In the process of assessing the submissions to this challenge, we developed several validation metrics, most of which require reference to the underlying ground truth volumes, but one which does not. These approaches allowed us to assess the similarity and accuracy in map quality, molecular motions, and distribution estimates of different submissions. These metrics and the efforts of all participants will help chart a path forward for the improvements of heterogeneity methods for cryo-EM and future challenges to test these new methods as they continue to be developed by the community.