CCB Seminar: A Bayesian Framework for Cryo-EM Heterogeneity Analysis using Regularized Covariance Estimation (Marc Gilles, Ph.D., Princeton University)

Speaker: Marc A. Gilles (Princeton University)

Title: A Bayesian Framework for Cryo-EM Heterogeneity Analysis using Regularized Covariance Estimation

Abstract: Proteins and the complexes they form are central to nearly all cellular processes. Their flexibility, expressed through a continuum of states, provides a window into their biological functions. Cryogenic-electron microscopy (cryo-EM) is an ideal tool to study these dynamic states as it captures specimens in non-crystalline conditions and enables high-resolution reconstructions. However, analyzing the heterogeneous distribution of conformations from cryo-EM data is challenging. Current methods face issues such as a lack of explainability, overfitting caused by lack of regularization, and a large number of parameters to tune; problems exacerbated by the lack of proper metrics to evaluate or compare heterogeneous reconstructions. To address these challenges, we present RECOVAR, a white-box method based on principal component analysis (PCA) computed via regularized covariance estimation that can resolve intricate heterogeneity with similar expressive power to neural networks with significantly lower computational demands.