Autocorrelation analysis for cryo-EM with sparsity constraints: Improved sample complexity and projection-based algorithms.

The number of noisy images required for molecular reconstruction in single-particle cryoelectron microscopy (cryo-EM) is governed by the autocorrelations of the observed, randomly oriented, noisy projection images. In this work, we consider the effect of imposing sparsity priors on the molecule. We use techniques from signal processing, optimization, and applied algebraic geometry to obtain theoretical and computational contributions for this challenging nonlinear inverse problem with sparsity constraints. We prove that molecular structures modeled as sums of Gaussians are uniquely determined by the second-order autocorrelation of their projection images, implying that the sample complexity is proportional to the square of the variance of the noise. This theory improves upon the nonsparse case, where the third-order autocorrelation is required for uniformly oriented particle images and the sample complexity scales with the cube of the noise variance. Furthermore, we build a computational framework to reconstruct molecular structures which are sparse in the wavelet basis. This method combines the sparse representation for the molecule with projection-based techniques used for phase retrieval in X-ray crystallography.

Quantitatively Visualizing Bipartite Datasets.

As experiments continue to increase in size and scope, a fundamental challenge of subsequent analyses is to recast the wealth of information into an intuitive and readily interpretable form. Often, each measurement conveys only the relationship between a pair of entries, and it is difficult to integrate these local interactions across a dataset to form a cohesive global picture. The classic localization problem tackles this question, transforming local measurements into a global map that reveals the underlying structure of a system. Here, we examine the more challenging bipartite localization problem, where pairwise distances are available only for bipartite data comprising two classes of entries (such as antibody-virus interactions, drug-cell potency, or user-rating profiles). We modify previous algorithms to solve bipartite localization and examine how each method behaves in the presence of noise, outliers, and partially observed data. As a proof of concept, we apply these algorithms to antibody-virus neutralization measurements to create a basis set of antibody behaviors, formalize how potently inhibiting some viruses necessitates weakly inhibiting other viruses, and quantify how often combinations of antibodies exhibit degenerate behavior.

NMR Assignment through Linear Programming.

Nuclear Magnetic Resonance (NMR) Spectroscopy is the second most used technique (after X-ray crystallography) for structural determination of proteins. A computational challenge in this technique involves solving a discrete optimization problem that assigns the resonance frequency to each atom in the protein. This paper introduces LIAN (LInear programming Assignment for NMR), a novel linear programming formulation of the problem which yields state-of-the-art results in simulated and experimental datasets.

Non-Iterative Rigid 2D/3D Point-Set Registration Using Semidefinite Programming.

We describe a convex programming framework for pose estimation in 2D/3D point-set registration with unknown point correspondences. We give two mixed-integer nonlinear program (MINLP) formulations of the 2D/3D registration problem when there are multiple 2D images, and propose convex relaxations for both the MINLPs to semidefinite programs that can be solved efficiently by interior point methods. Our approach to the 2D/3D registration problem is non-iterative in nature as we jointly solve for pose and correspondence. Furthermore, these convex programs can readily incorporate feature descriptors of points to enhance registration results. We prove that the convex programs exactly recover the solution to the MINLPs under certain noiseless condition. We apply these formulations to the registration of 3D models of coronary vessels to their 2D projections obtained from multiple intra-operative fluoroscopic images. For this application, we experimentally corroborate the exact recovery property in the absence of noise and further demonstrate robustness of the convex programs in the presence of noise.