Progress and Pitfalls in Free Energy Landscapes from Cryo-EM

Join us for our next in-person event, hosted at NYU's Simons Center where we will hear from Sonya Hanson at Flatiron Institute.

Since the resolution revolution in cryo-EM the method has become a dominant technique for high resolution structure determination of biological macromolecules. However, it is often still treated as a method for obtaining individual high resolution structures, as had been the necessity for decades with X-ray crystallography, despite the potential access cryo-EM gives to conformational ensembles. Here we delve into progress and pitfalls toward the analysis of conformational heterogeneity of single particle cryo-EM datasets. These methods have the potential to give access to not only the structures of metastable states but their populations, however understanding the caveats of different methodologies is critical. We have taken two approaches to compare and contrast different methods to extract conformational heterogeneity from cryo-EM: 1) analyzing a single experimental dataset using the variety of methods available and 2) conducting a conformational heterogeneity challenge for the cryo-EM community in which groups across the world participated using their own algorithms to extract states and populations. Finally, we conclude with a discussion of our own future directions for methods development in this area, and how combining cryo-EM with molecular dynamics simulation is essential.

Thank you very much to the NYU Simons Center for hosting this event! The NYU Simons Center for Computational Physical Chemistry aims to be a hub for computational physical chemistry. Spanning many disciplines — mathematics, physics, chemistry, biology, and computer science — the Simons Center promotes the use of computational, physics-based approaches to solving problems, fosters collaboration across the global computational chemistry community, and works to expand and strengthen the diversity of participants in this field.