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Abstract The Fourier shell correlation (FSC) is a measure of the similarity between two signals computed over corresponding shells in the frequency domain and has broad applications in microscopy. In structural biology, the FSC is ubiquitous in methods for validation, resolution determination, and signal enhancement. Computing the FSC usually requires two independent measurements of the same underlying signal, which can be limiting for some applications. Here, we analyze and extend on an approach to estimate the FSC from a single measurement. In particular, we derive the necessary conditions required to estimate the FSC from downsampled versions of a single noisy measurement. These conditions reveal additional corrections which we implement to increase the applicability of the method. We then illustrate two applications of our approach, first as an estimate of the global resolution from a single 3-D structure and second as a data-driven method for denoising tomographic reconstructions in electron cryo-tomography. These results provide general guidelines for computing the FSC from a single measurement and suggest new applications of the FSC in microscopy. 

Abstract In synchronization problems, the goal is to estimate elements of a group from noisy measurements of their ratios. A popular estimation method for synchronization is the spectral method. It extracts the group elements from eigenvectors of a block matrix formed from the measurements. The eigenvectors must be projected, or ‘rounded’, onto the group. The rounding procedures are constructed ad hoc and increasingly so when applied to synchronization problems over non-compact groups. In this paper, we develop a spectral approach to synchronization over the non-compact group $$\mathrm{SE}(3)$$, the group of rigid motions of $$\mathbb{R}^{3}$$. We based our method on embedding $$\mathrm{SE}(3)$$ into the algebra of dual quaternions, which has deep algebraic connections with the group $$\mathrm{SE}(3)$$. These connections suggest a natural rounding procedure considerably more straightforward than the current state of the art for spectral $$\mathrm{SE}(3)$$ synchronization, which uses a matrix embedding of $$\mathrm{SE}(3)$$. We show by numerical experiments that our approach yields comparable results with the current state of the art in $$\mathrm{SE}(3)$$ synchronization via the spectral method. Thus, our approach reaps the benefits of the dual quaternion embedding of $$\mathrm{SE}(3)$$ while yielding estimators of similar quality. 

Abstract In this article, we propose an algorithm for aligning three-dimensional objects when represented as density maps, motivated by applications in cryogenic electron microscopy. The algorithm is based on minimizing the 1-Wasserstein distance between the density maps after a rigid transformation. The induced loss function enjoys a more benign landscape than its Euclidean counterpart and Bayesian optimization is employed for computation. Numerical experiments show improved accuracy and efficiency over existing algorithms on the alignment of real protein molecules. In the context of aligning heterogeneous pairs, we illustrate a potential need for new distance functions. 

Abstract Single-particle cryogenic electron microscopy (cryo-EM) is an imaging technique capable of recovering the high-resolution three-dimensional (3D) structure of biological macromolecules from many noisy and randomly oriented projection images. One notable approach to 3D reconstruction, known as Kam’s method, relies on the moments of the two-dimensional (2D) images. Inspired by Kam’s method, we introduce a rotationally invariant metric between two molecular structures, which does not require 3D alignment. Further, we introduce a metric between a stack of projection images and a molecular structure, which is invariant to rotations and reflections and does not require performing 3D reconstruction. Additionally, the latter metric does not assume a uniform distribution of viewing angles. We demonstrate the uses of the new metrics on synthetic and experimental datasets, highlighting their ability to measure structural similarity. 

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 noncrystalline conditions and enables high-resolution reconstructions. However, analyzing the heterogeneous distributions of conformations from cryo-EM data is challenging. We present RECOVAR, a method for analyzing these distributions based on principal component analysis (PCA) computed using a REgularized COVARiance estimator. RECOVAR is fast, robust, interpretable, expressive, and competitive with state-of-the-art neural network methods on heterogeneous cryo-EM datasets. The regularized covariance method efficiently computes a large number of high-resolution principal components that can encode rich heterogeneous distributions of conformations and does so robustly thanks to an automatic regularization scheme. The reconstruction method based on adaptive kernel regression resolves conformational states to a higher resolution than all other tested methods on extensive independent benchmarks while remaining highly interpretable. Additionally, we exploit favorable properties of the PCA embedding to estimate the conformational density accurately. This density allows for better interpretability of the latent space by identifying stable states and low free-energy motions. Finally, we present a scheme to navigate the high-dimensional latent space by automatically identifying these low free-energy trajectories. We make the code freely available athttps://github.com/ma-gilles/recovar.