257 Publications

Conformational heterogeneity and probability distributions from single-particle cryo-electron microscopy

Single-particle cryo-electron microscopy (cryo-EM) is a technique that takes projection images of biomolecules frozen at cryogenic temperatures. A major advantage of this technique is its ability to image single biomolecules in heterogeneous conformations. While this poses a challenge for data analysis, recent algorithmic advances have enabled the recovery of heterogeneous conformations from the noisy imaging data. Here, we review methods for the reconstruction and heterogeneity analysis of cryo-EM images, ranging from linear-transformation-based methods to nonlinear deep generative models. We overview the dimensionality-reduction techniques used in heterogeneous 3D reconstruction methods and specify what information each method can infer from the data. Then, we review the methods that use cryo-EM images to estimate probability distributions over conformations in reduced subspaces or predefined by atomistic simulations. We conclude with the ongoing challenges for the cryo-EM community.

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Implicit Adaptive Mesh Refinement for Dispersive Tsunami Propagation

M. Berger, Randall J. LeVeque

We present an algorithm to solve the dispersive depth-averaged Serre-Green-Naghdi (SGN) equations using patch-based adaptive mesh refinement. These equations require adding additional higher derivative terms to the nonlinear shallow water equations. This has been implemented as a new component of the open source GeoClaw software that is widely used for modeling tsunamis, storm surge, and related hazards, improving its accuracy on shorter wavelength phenomena. The equations require the solution of an elliptic system at each time step. The adaptive algorithm allows different time steps on different refinement levels, and solves the implicit equations level by level. Computational examples are presented to illustrate the stability and accuracy on a radially symmetric test case and two realistic tsunami modeling problems, including a hypothetical asteroid impact creating a short wavelength tsunami for which dispersive terms are necessary.

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July 11, 2023

Low-rank Green’s function representations applied to dynamical mean-field theory

Nan Sheng , Alexander Hampel, Sophie Beck, Olivier Parcollet, Nils Wentzell, J. Kaye, Kun Chen

Several recent works have introduced highly compact representations of single-particle Green's functions in the imaginary time and Matsubara frequency domains, as well as efficient interpolation grids used to recover the representations. In particular, the intermediate representation with sparse sampling and the discrete Lehmann representation (DLR) make use of low rank compression techniques to obtain optimal approximations with controllable accuracy. We consider the use of the DLR in dynamical mean-field theory (DMFT) calculations, and in particular show that the standard full Matsubara frequency grid can be replaced by the compact grid of DLR Matsubara frequency nodes. We test the performance of the method for a DMFT calculation of Sr$_2$RuO$_4$ at temperature $50$K using a continuous-time quantum Monte Carlo impurity solver, and demonstrate that Matsubara frequency quantities can be represented on a grid of only 36 nodes with no reduction in accuracy, or increase in the number of self-consistent iterations, despite the presence of significant Monte Carlo noise.

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A Stochastic Proximal Polyak Step Size

Fabian Schaipp, R. M. Gower, Michael Ulbrich

Recently, the stochastic Polyak step size (SPS) has emerged as a competitive adaptive step size scheme for stochastic gradient descent. Here we develop ProxSPS, a proximal variant of SPS that can handle regularization terms. Developing a proximal variant of SPS is particularly important, since SPS requires a lower bound of the objective function to work well. When the objective function is the sum of a loss and a regularizer, available estimates of a lower bound of the sum can be loose. In contrast, ProxSPS only requires a lower bound for the loss which is often readily available. As a consequence, we show that ProxSPS is easier to tune and more stable in the presence of regularization. Furthermore for image classification tasks, ProxSPS performs as well as AdamW with little to no tuning, and results in a network with smaller weight parameters. We also provide an extensive convergence analysis for ProxSPS that includes the non-smooth, smooth, weakly convex and strongly convex setting.

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May 4, 2023

Finding and Representing Solutions to Transmission Problems for Open Channels

We introduce a layer potential representation for the solution of the transmission problem defined by two dielectric channels, or open waveguides, meeting along the straight-line interface, {x1=0}. The main observation is that the outgoing fundamental solution for the operator Δ+k21+q(x2), acting on functions defined in ℝ2, is easily constructed using the Fourier transform in the x1-variable and the elementary theory of ordinary differential equations. These fundamental solutions can then be used to represent the solution to the transmission problem in half planes. The transmission boundary conditions lead to integral equations along the intersection of the half planes, which, in our normalization, is the x2-axis. We show that, in appropriate Banach spaces, these integral equations are Fredholm equations of second kind, which are therefore generically solvable. We then show that the solutions satisfy an analogue of the Sommerfeld radiation condition that follows from work of Isozaki, Melrose, Vasy, et al. This formulation suggests practicable numerical methods to approximately solve this class of problems.

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April 24, 2023

A fast, accurate and easy to implement Kapur — Rokhlin quadrature scheme for singular integrals in axisymmetric geometries

Evan Toler, A.J. Cerfon, D. Malhotra

Many applications in magnetic confinement fusion require the efficient calculation of surface integrals with singular integrands. The singularity subtraction approaches typically used to handle such singularities are complicated to implement and low-order accurate. In contrast, we demonstrate that the Kapur–Rokhlin quadrature scheme is well-suited for the logarithmically singular integrals encountered for a toroidally axisymmetric confinement system, is easy to implement and is high-order accurate. As an illustration, we show how to apply this quadrature scheme for the efficient and accurate calculation of the normal component of the magnetic field due to the plasma current on the plasma boundary, via the virtual-casing principle.

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Automatic, high-order, and adaptive algorithms for Brillouin zone integration

J. Kaye, Sophie Beck, A. Barnett, Lorenzo Van Muñoz, Olivier Parcollet

We present efficient methods for Brillouin zone integration with a non-zero but possibly very small broadening factor η, focusing on cases in which downfolded Hamiltonians can be evaluated efficiently using Wannier interpolation. We describe robust, high-order accurate algorithms automating convergence to a user-specified error tolerance ε, emphasizing an efficient computational scaling with respect to η. After analyzing the standard equispaced integration method, applicable in the case of large broadening, we describe a simple iterated adaptive integration algorithm effective in the small η regime. Its computational cost scales as \(\)(log3(η−1)) as η→0+ in three dimensions, as opposed to \(\)(η−3) for equispaced integration. We argue that, by contrast, tree-based adaptive integration methods scale only as \(\)(log(η−1)/η2) for typical Brillouin zone integrals. In addition to its favorable scaling, the iterated adaptive algorithm is straightforward to implement, particularly for integration on the irreducible Brillouin zone, for which it avoids the tetrahedral meshes required for tree-based schemes. We illustrate the algorithms by calculating the spectral function of SrVO3 with broadening on the meV scale.

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Folding and modulation of the helical conformation of Glycophorin A by point mutations

Pei-Yin Lee, A. Sahoo, Silvina Matysiak

Transmembrane helix folding and self-association play important roles in biological signaling and transportation pathways across biomembranes. With molecular simulations, studies to explore the structural biochemistry of this process have been limited to focusing on individual fragments of this process – either helix formation or dimerization. While at an atomistic resolution, it can be prohibitive to access long spatio-temporal scales, at the coarse grained (CG) level, current methods either employ additional constraints to prevent spontaneous unfolding or have a low resolution on sidechain beads that restricts the study of dimer disruption caused by mutations. To address these research gaps, in this work, we apply our recent, in-house developed CG model (ProMPT) to study the folding and dimerization of Glycophorin A (GpA) and its mutants in the presence of Dodecyl-phosphocholine (DPC) micelles. Our results first validate the two-stage model that folding and dimerization are independent events for transmembrane helices and found a positive correlation between helix folding and DPC-peptide contacts. The wild type (WT) GpA is observed to be a right-handed dimer with specific GxxxG contacts, which agrees with experimental findings. Specific point mutations reveal several features responsible for the structural stability of GpA. While the T87L mutant forms anti-parallel dimers due to an absence of T87 interhelical hydrogen bonds, a slight loss in helicity and a hinge-like feature at the GxxxG region develops for the G79L mutant. We note that the local changes in the hydrophobic environment, affected by the point mutation, contribute to the development of this helical bend. This work presents a holistic overview of the structural stability of GpA in a micellar environment, while taking secondary structural fluctuations into account. Moreover, it presents opportunities for applications of computationally efficient CG models to study conformational alterations of transmembrane proteins that have physiological relevance.

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A Bregman-Kaczmarz method for nonlinear systems of equations

R. M. Gower, Dirk A. Lorenz, Maximilian Winkler

We propose a new randomized method for solving systems of nonlinear equations, which can find sparse solutions or solutions under certain simple constraints. The scheme only takes gradients of component functions and uses Bregman projections onto the solution space of a Newton equation. In the special case of euclidean projections, the method is known as nonlinear Kaczmarz method. Furthermore, if the component functions are nonnegative, we are in the setting of optimization under the interpolation assumption and the method reduces to SGD with the recently proposed stochastic Polyak step size. For general Bregman projections, our method is a stochastic mirror descent with a novel adaptive step size. We prove that in the convex setting each iteration of our method results in a smaller Bregman distance to exact solutions as compared to the standard Polyak step. Our generalization to Bregman projections comes with the price that a convex one-dimensional optimization problem needs to be solved in each iteration. This can typically be done with globalized Newton iterations. Convergence is proved in two classical settings of nonlinearity: for convex nonnegative functions and locally for functions which fulfill the tangential cone condition. Finally, we show examples in which the proposed method outperforms similar methods with the same memory requirements.

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March 15, 2023

Microscopic Theory, Analysis, and Interpretation of Conductance Histograms in Molecular Junctions

Leopoldo Mejía, P. Cossio, Ignacio Franco

Molecular electronics break-junction experiments are widely used to investigate fundamental physics and chemistry at the nanoscale. Reproducibility in these experiments relies on measuring conductance on thousands of freshly formed molecular junctions, yielding a broad histogram of conductance events. Experiments typically focus on the most probable conductance, while the information content of the conductance histogram has remained unclear. Here, we develop a theory for the conductance histogram by merging the theory of force-spectroscopy with molecular conductance. To do so, we propose a microscopic model of the junction evolution under the modulation of external mechanical forces and combine it with the statistics of junction rupture and formation. Our formulation focuses on contributions to the conductance dispersion that emerge due to changes in the conductance during mechanical manipulation. The final shape of the histogram is determined by the statistics of junction rupture and formation. The procedure yields analytical equations for the conductance histogram in terms of parameters that describe the free-energy profile of the junction, its mechanical manipulation, and the ability of the molecule to transport charge. All physical parameters that define our microscopic model can be extracted from separate conductance and rupture force measurements on molecular junctions. Our theory accurately fits experimental conductance histograms and augments the information content that can be extracted from experiments. Further, the predicted behavior with respect to physical parameters can be used to design experiments with narrower conductance distribution and to test the range of validity of the model.

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March 10, 2023
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