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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., Comment: 28 pages, 10 figures

Single-particle reconstruction in cryo-electron microscopy (cryo-EM) is an increasingly popular technique for determining the 3-D structure of a molecule from several noisy 2-D projections images taken at unknown viewing angles. Most reconstruction algorithms require a low-resolution initialization for the 3-D structure, which is the goal of ab initio modeling. Suggested by Zvi Kam in 1980, the method of moments (MoM) offers one approach, wherein low-order statistics of the 2-D images are computed and a 3-D structure is estimated by solving a system of polynomial equations. Unfortunately, Kam's method suffers from restrictive assumptions, most notably that viewing angles should be distributed uniformly. Often unrealistic, uniformity entails the computation of higher-order correlations, as in this case first and second moments fail to determine the 3-D structure. In the present paper, we remove this hypothesis, by permitting an unknown, non-uniform distribution of viewing angles in MoM. Perhaps surprisingly, we show that this case is statistically easier than the uniform case, as now first and second moments generically suffice to determine low-resolution expansions of the molecule. In the idealized setting of a known, non-uniform distribution, we find an efficient provable algorithm inverting first and second moments. For unknown, non-uniform distributions, we use non-convex optimization methods to solve for both the molecule and distribution., Comment: 41 pages. v2: additional numerical experiments, appendices edited, other updates

Single-Particle Reconstruction (SPR) in Cryo-Electron Microscopy (cryo-EM) is the task of estimating the 3D structure of a molecule from a set of noisy 2D projections, taken from unknown viewing directions. Many algorithms for SPR start from an initial reference molecule, and alternate between refining the estimated viewing angles given the molecule, and refining the molecule given the viewing angles. This scheme is called iterative refinement. Reliance on an initial, user-chosen reference introduces model bias, and poor initialization can lead to slow convergence. Furthermore, since no ground truth is available for an unsolved molecule, it is difficult to validate the obtained results. This creates the need for high quality ab initio models that can be quickly obtained from experimental data with minimal priors, and which can also be used for validation. We propose a procedure to obtain such an ab initio model directly from raw data using Kam's autocorrelation method. Kam's method has been known since 1980, but it leads to an underdetermined system, with missing orthogonal matrices. Until now, this system has been solved only for special cases, such as highly symmetric molecules or molecules for which a homologous structure was already available. In this paper, we show that knowledge of just two clean projections is sufficient to guarantee a unique solution to the system. This system is solved by an optimization-based heuristic. For the first time, we are then able to obtain a low-resolution ab initio model of an asymmetric molecule directly from raw data, without 2D class averaging and without tilting. Numerical results are presented on both synthetic and experimental data.

The matching problem between two adjacency matrices can be formulated as the NP-hard quadratic assignment problem (QAP). Previous work on semidefinite programming (SDP) relaxations to the QAP have produced solutions that are often tight in practice, but such SDPs typically scale badly, involving matrix variables of dimension $n^2$ where n is the number of nodes. To achieve a speed up, we propose a further relaxation of the SDP involving a number of positive semidefinite matrices of dimension $\mathcal{O}(n)$ no greater than the number of edges in one of the graphs. The relaxation can be further strengthened by considering cliques in the graph, instead of edges. The dual problem of this novel relaxation has a natural three-block structure that can be solved via a convergent Augmented Direction Method of Multipliers (ADMM) in a distributed manner, where the most expensive step per iteration is computing the eigendecomposition of matrices of dimension $\mathcal{O}(n)$. The new SDP relaxation produces strong bounds on quadratic assignment problems where one of the graphs is sparse with reduced computational complexity and running times, and can be used in the context of nuclear magnetic resonance spectroscopy (NMR) to tackle the assignment problem., Comment: 31 pages

Group contraction is an algebraic map that relates two classes of Lie groups by a limiting process. We utilize this notion for the compactification of the class of Cartan motion groups. The compactification process is then applied to reduce a non-compact synchronization problem to a problem where the solution can be obtained by means of a unitary, faithful representation. We describe this method of synchronization via contraction in detail and analyze several important aspects of this application. One important special case of Cartan motion groups is the group of rigid motions, also called the special Euclidean group. We thoroughly discuss the synchronization over this group and show numerically the advantages of our approach compared to some current state-of-the-art synchronization methods on both synthetic and real data.

One of the difficulties in 3D reconstruction of molecules from images in single particle Cryo-Electron Microscopy (Cryo-EM), in addition to high levels of noise and unknown image orientations, is heterogeneity in samples: in many cases, the samples contain a mixture of molecules, or multiple conformations of one molecule. Many algorithms for the reconstruction of molecules from images in heterogeneous Cryo-EM experiments are based on iterative approximations of the molecules in a non-convex optimization that is prone to reaching suboptimal local minima. Other algorithms require an alignment in order to perform classification, or vice versa. The recently introduced Non-Unique Games framework provides a representation theoretic approach to studying problems of alignment over compact groups, and offers convex relaxations for alignment problems which are formulated as semidefinite programs (SDPs) with certificates of global optimality under certain circumstances. In this manuscript, we propose to extend Non-Unique Games to the problem of simultaneous alignment and classification with the goal of simultaneously classifying Cryo-EM images and aligning them within their respective classes. Our proposed approach can also be extended to the case of continuous heterogeneity.

We revisit the problem of protein structure determination from geometrical restraints from NMR, using convex optimization. It is well-known that the NP-hard distance geometry problem of determining atomic positions from pairwise distance restraints can be relaxed into a convex semidefinite program. Often the NOE distance restraints are too imprecise and sparse for accurate structure determination. Residual dipolar coupling (RDC) measurements provide additional geometric information on the angles between atom-pair directions and axes of the principal-axis-frame. The optimization problem involving RDC is highly non-convex and requires a good initialization even within the simulated annealing framework. In this paper, we model the protein backbone as an articulated structure composed of rigid units. Determining the rotation of each rigid unit gives the full protein structure. We propose solving the non-convex optimization problems using the sum-of-squares (SOS) hierarchy. The two algorithms - RDC-SOS and RDC-NOE-SOS, have polynomial time complexity in the number of amino-acid residues and run efficiently on a standard desktop. In many instances, the proposed methods exactly recover the solution to the original non-convex optimization problem. We introduce a statistical tool, the Cramer-Rao bound (CRB), to provide an information theoretic bound on the highest resolution one can hope to achieve when determining protein structure from noisy measurements using any methodology. Our simulation results show that when the RDC measurements are corrupted by Gaussian noise of realistic variance, both SOS based algorithms attain the CRB. We successfully apply our method in a divide-and-conquer fashion to determine the structure of ubiquitin from experimental NOE and RDC measurements, achieving more accurate and faster reconstructions compared to the current state of the art., Comment: 41 pages, 5 figures

Motivated by a certain molecular reconstruction methodology in cryo-electron microscopy, we consider the problem of solving a linear system with two unknown orthogonal matrices, which is a generalization of the well-known orthogonal Procrustes problem. We propose an algorithm based on a semi-definite programming (SDP) relaxation, and give a theoretical guarantee for its performance. Both theoretically and empirically, the proposed algorithm performs better than the na\"{i}ve approach of solving the linear system directly without the orthogonal constraints. We also consider the generalization to linear systems with more than two unknown orthogonal matrices.

Let $\mathcal{G}$ be a compact group and let $f_{ij} \in L^2(\mathcal{G})$. We define the Non-Unique Games (NUG) problem as finding $g_1,\dots,g_n \in \mathcal{G}$ to minimize $\sum_{i,j=1}^n f_{ij} \left( g_i g_j^{-1}\right)$. We devise a relaxation of the NUG problem to a semidefinite program (SDP) by taking the Fourier transform of $f_{ij}$ over $\mathcal{G}$, which can then be solved efficiently. The NUG framework can be seen as a generalization of the little Grothendieck problem over the orthogonal group and the Unique Games problem and includes many practically relevant problems, such as the maximum likelihood estimator} to registering bandlimited functions over the unit sphere in $d$-dimensions and orientation estimation in cryo-Electron Microscopy.

Maximum likelihood estimation problems are, in general, intractable optimization problems. As a result, it is common to approximate the maximum likelihood estimator (MLE) using convex relaxations. In some cases, the relaxation is tight: it recovers the true MLE. Most tightness proofs only apply to situations where the MLE exactly recovers a planted solution (known to the analyst). It is then sufficient to establish that the optimality conditions hold at the planted signal. In this paper, we study an estimation problem (angular synchronization) for which the MLE is not a simple function of the planted solution, yet for which the convex relaxation is tight. To establish tightness in this context, the proof is less direct because the point at which to verify optimality conditions is not known explicitly. Angular synchronization consists in estimating a collection of $n$ phases, given noisy measurements of the pairwise relative phases. The MLE for angular synchronization is the solution of a (hard) non-bipartite Grothendieck problem over the complex numbers. We consider a stochastic model for the data: a planted signal (that is, a ground truth set of phases) is corrupted with non-adversarial random noise. Even though the MLE does not coincide with the planted signal, we show that the classical semidefinite relaxation for it is tight, with high probability. This holds even for high levels of noise., Comment: 2 figures

We have observed an interesting, yet unexplained, phenomenon: Semidefinite programming (SDP) based relaxations of maximum likelihood estimators (MLE) tend to be tight in recovery problems with noisy data, even when MLE cannot exactly recover the ground truth. Several results establish tightness of SDP based relaxations in the regime where exact recovery from MLE is possible. However, to the best of our knowledge, their tightness is not understood beyond this regime. As an illustrative example, we focus on the generalized Procrustes problem.

In this paper, we describe an algorithm for sensor network localization (SNL) that proceeds by dividing the whole network into smaller subnetworks, then localizes them in parallel using some fast and accurate algorithm, and finally registers the localized subnetworks in a global coordinate system. We demonstrate that this divide-and-conquer algorithm can be used to leverage existing high-precision SNL algorithms to large-scale networks, which could otherwise only be applied to small-to-medium sized networks. The main contribution of this paper concerns the final registration phase. In particular, we consider a least-squares formulation of the registration problem (both with and without anchor constraints) and demonstrate how this otherwise non-convex problem can be relaxed into a tractable convex program. We provide some preliminary simulation results for large-scale SNL demonstrating that the proposed registration algorithm (together with an accurate localization scheme) offers a good tradeoff between run time and accuracy., Comment: 5 pages, 8 figures, 1 table. To appear in Proc. IEEE International Conference on Acoustics, Speech, and Signal Processing, April 19-24, 2015

The little Grothendieck problem consists of maximizing $\sum_{ij}C_{ij}x_ix_j$ over binary variables $x_i\in\{\pm1\}$, where C is a positive semidefinite matrix. In this paper we focus on a natural generalization of this problem, the little Grothendieck problem over the orthogonal group. Given C a dn x dn positive semidefinite matrix, the objective is to maximize $\sum_{ij}Tr (C_{ij}^TO_iO_j^T)$ restricting $O_i$ to take values in the group of orthogonal matrices, where $C_{ij}$ denotes the (ij)-th d x d block of C. We propose an approximation algorithm, which we refer to as Orthogonal-Cut, to solve this problem and show a constant approximation ratio. Our method is based on semidefinite programming. For a given $d\geq 1$, we show a constant approximation ratio of $\alpha_{R}(d)^2$, where $\alpha_{R}(d)$ is the expected average singular value of a d x d matrix with random Gaussian $N(0,1/d)$ i.i.d. entries. For d=1 we recover the known $\alpha_{R}(1)^2=2/\pi$ approximation guarantee for the classical little Grothendieck problem. Our algorithm and analysis naturally extends to the complex valued case also providing a constant approximation ratio for the analogous problem over the Unitary Group. Orthogonal-Cut also serves as an approximation algorithm for several applications, including the Procrustes problem where it improves over the best previously known approximation ratio of~$\frac1{2\sqrt{2}}$. The little Grothendieck problem falls under the class of problems approximated by a recent algorithm proposed in the context of the non-commutative Grothendieck inequality. Nonetheless, our approach is simpler and it provides a more efficient algorithm with better approximation ratios and matching integrality gaps. Finally, we also provide an improved approximation algorithm for the more general little Grothendieck problem over the orthogonal (or unitary) group with rank constraints., Comment: Updates in version 2: extension to the complex valued (unitary group) case, sharper lower bounds on the approximation ratios, matching integrality gap, and a generalized rank constrained version of the problem. Updates in version 3: Improvement on the exposition

A major challenge in single particle reconstruction methods using cryo-electron microscopy is to attain a resolution sufficient to interpret fine details in three-dimensional (3D) macromolecular structures. Obtaining high resolution 3D reconstructions is difficult due to unknown orientations and positions of the imaged particles, possible incomplete coverage of the viewing directions, high level of noise in the projection images, and limiting effects of the contrast transfer function of the electron microscope. In this paper, we focus on the 3D reconstruction problem from projection images assuming an existing estimate for their orientations and positions. We propose a fast and accurate Fourier-based Iterative Reconstruction Method (FIRM) that exploits the Toeplitz structure of the operator ${\bf A}^{*}{\bf A}$, where $\bf A$ is the forward projector and ${\bf A}^{*}$ is the back projector. The operator ${\bf A}^{*}{\bf A}$ is equivalent to a convolution with a kernel. The kernel is pre-computed using the non-uniform Fast Fourier Transform and is efficiently applied in each iteration step. The iterations by FIRM are therefore considerably faster than those of traditional iterative algebraic approaches, while maintaining the same accuracy even when the viewing directions are unevenly distributed. The time complexity of FIRM is comparable to the direct Fourier inversion method. Moreover, FIRM combines images from different defocus groups simultaneously and can handle a wide range of regularization terms. We provide experimental results on simulated data that demonstrate the speed and accuracy of FIRM in comparison with current methods.

Consider $N$ points in $\mathbb{R}^d$ and $M$ local coordinate systems that are related through unknown rigid transforms. For each point we are given (possibly noisy) measurements of its local coordinates in some of the coordinate systems. Alternatively, for each coordinate system, we observe the coordinates of a subset of the points. The problem of estimating the global coordinates of the $N$ points (up to a rigid transform) from such measurements comes up in distributed approaches to molecular conformation and sensor network localization, and also in computer vision and graphics. The least-squares formulation of this problem, though non-convex, has a well known closed-form solution when $M=2$ (based on the singular value decomposition). However, no closed form solution is known for $M\geq 3$. In this paper, we demonstrate how the least-squares formulation can be relaxed into a convex program, namely a semidefinite program (SDP). By setting up connections between the uniqueness of this SDP and results from rigidity theory, we prove conditions for exact and stable recovery for the SDP relaxation. In particular, we prove that the SDP relaxation can guarantee recovery under more adversarial conditions compared to earlier proposed spectral relaxations, and derive error bounds for the registration error incurred by the SDP relaxation. We also present results of numerical experiments on simulated data to confirm the theoretical findings. We empirically demonstrate that (a) unlike the spectral relaxation, the relaxation gap is mostly zero for the semidefinite program (i.e., we are able to solve the original non-convex least-squares problem) up to a certain noise threshold, and (b) the semidefinite program performs significantly better than spectral and manifold-optimization methods, particularly at large noise levels., Comment: 33 pages, 12 figures. To appear in SIAM Journal on Optimization

A major challenge in single particle reconstruction from cryo-electron microscopy is to establish a reliable ab-initio three-dimensional model using two-dimensional projection images with unknown orientations. Common-lines based methods estimate the orientations without additional geometric information. However, such methods fail when the detection rate of common-lines is too low due to the high level of noise in the images. An approximation to the least squares global self consistency error was obtained using convex relaxation by semidefinite programming. In this paper we introduce a more robust global self consistency error and show that the corresponding optimization problem can be solved via semidefinite relaxation. In order to prevent artificial clustering of the estimated viewing directions, we further introduce a spectral norm term that is added as a constraint or as a regularization term to the relaxed minimization problem. The resulted problems are solved by using either the alternating direction method of multipliers or an iteratively reweighted least squares procedure. Numerical experiments with both simulated and real images demonstrate that the proposed methods significantly reduce the orientation estimation error when the detection rate of common-lines is low.