1429 Publications

Ensemble reweighting using Cryo-EM particles

P. Tang, B. Carpenter, D. Silva-Sánchez, J. Giraldo-Barreto, S. Hanson, A. Barnett, E. Thiede, P. Cossio

Cryo-electron microscopy (cryo-EM) has recently become a premier method for obtaining high-resolution structures of biological macromolecules. However, it is limited to biomolecular samples with low conformational heterogeneity, where all the conformations can be well-sampled at many projection angles. While cryo-EM technically provides single-molecule data for heterogeneous molecules, most existing reconstruction tools cannot extract the full distribution of possible molecular configurations. To overcome these limitations, we build on a prior Bayesian approach and develop an ensemble refinement framework that estimates the ensemble density from a set of cryo-EM particles by reweighting a prior ensemble of conformations, e.g., from molecular dynamics simulations or structure prediction tools. Our work is a general approach to recovering the equilibrium probability density of the biomolecule directly in conformational space from single-molecule data. To validate the framework, we study the extraction of state populations and free energies for a simple toy model and from synthetic cryo-EM images of a simulated protein that explores multiple folded and unfolded conformations.

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December 10, 2022

SARS-CoV-2 Outbreak Dynamics in an Isolated US Military Recruit Training Center With Rigorous Prevention Measures

Rhonda A. Lizewski, R. Sealfon, O. Troyanskaya, et al.

Marine recruits training at Parris Island experienced an unexpectedly high rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite preventive measures including a supervised, 2-week, pre-entry quarantine. We characterize SARS-CoV-2 transmission in this cohort.

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How to Design Peptides

Joseph Dodd-O, Amanda M Acevedo-Jake, V. Mulligan, et al.

Novel design of proteins to target receptors for treatment or tissue augmentation has come to the fore owing to advancements in computing power, modeling frameworks, and translational successes. Shorter proteins, or peptides, can offer combinatorial synergies with dendrimer, polymer, or other peptide carriers for enhanced local signaling, which larger proteins may sterically hinder. Here, we present a generalized method for designing a novel peptide. We first show how to create a script protocol that can be used to iteratively optimize and screen novel peptide sequences for binding a target protein. We present a step-by-step introduction to utilizing file repositories, data bases, and the Rosetta software suite. RosettaScripts, an .xml interface that allows for sequential functions to be performed, is used to order the functions for repeatable performance. These strategies may lead to more groups venturing into computational design, which may result in synergies from artificial intelligence/machine learning (AI/ML) to phage display and screening. Importantly, the beginner is expected to be able to design their first peptide ligand and begin their journey in peptide drug discovery. Generally, these peptides potentially could be used to interact with any enzyme or receptor, for example, in the study of chemokines and their interactions with glycosoaminoglycans and their receptors.

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Incompressible active phases at an interface. Part 1. Formulation and axisymmetric odd flows

L. Jia, William T. M. Irvine, M. Shelley

Inspired by the recent realization of a two-dimensional (2-D) chiral fluid as an active monolayer droplet moving atop a 3-D Stokesian fluid, we formulate mathematically its free-boundary dynamics. The surface droplet is described as a general 2-D linear, incompressible and isotropic fluid, having a viscous shear stress, an active chiral driving stress and a Hall stress allowed by the lack of time-reversal symmetry. The droplet interacts with itself through its driven internal mechanics and by driving flows in the underlying 3-D Stokes phase. We pose the dynamics as the solution to a singular integral–differential equation, over the droplet surface, using the mapping from surface stress to surface velocity for the 3-D Stokes equations. Specializing to the case of axisymmetric droplets, exact representations for the chiral surface flow are given in terms of solutions to a singular integral equation, solved using both analytical and numerical techniques. For a disc-shaped monolayer, we additionally employ a semi-analytical solution that hinges on an orthogonal basis of Bessel functions and allows for efficient computation of the monolayer velocity field, which ranges from a nearly solid-body rotation to a unidirectional edge current, depending on the subphase depth and the Saffman–Delbrück length. Except in the near-wall limit, these solutions have divergent surface shear stresses at droplet boundaries, a signature of systems with codimension-one domains embedded in a 3-D medium. We further investigate the effect of a Hall viscosity, which couples radial and transverse surface velocity components, on the dynamics of a closing cavity. Hall stresses are seen to drive inward radial motion, even in the absence of edge tension.

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The physical basis of self-organization of the mammalian oocyte spindle

Colm P Kelleher, D. Needleman

To prepare gametes with the appropriate number of chromosomes, mammalian oocytes undergo two sequential cell divisions. During each division, a large, long-lived, microtubule-based organelle called the meiotic spindle assembles around condensed chromosomes. Although meiotic spindles have been intensively studied for several decades, as force-generating mechanical objects, they remain very poorly understood. In materials physics, coarse-grained theories have been essential in understanding the large-scale behavior of systems composed of many interacting particles. It is unclear, however, if this approach can succeed in capturing the properties of active, biochemically complex, living materials like the spindle. Here, we show that a class of models based on nematic liquid crystal theory can describe important aspects of the organelle-scale structure and dynamics of spindles in living mouse oocytes. Using our models to interpret quantitative polarization microscopy data, we measure for the first time material properties relating to stress propagation in living oocytes, including the nematic diffusivities corresponding to splay and bend deformations. Unlike the reconstituted amphibian spindles that were previously studied in vitro, nematic elastic stress is exponentially screened in the microtubule network of living mammalian oocytes, with a screening length of order one micron. This observation can be explained by the relatively high volume fraction of embedded chromosomes in mammalian meiotic spindles, which cause long voids in the microtubule network and so disrupt orientational stress propagation.

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November 2, 2022

Pre-infection antiviral innate immunity contributes to sex differences in SARS-CoV-2 infection

Male sex is a major risk factor for SARS-CoV-2 infection severity. To understand the basis for this sex difference, we studied SARS-CoV-2 infection in a young adult cohort of United States Marine recruits. Among 2,641 male and 244 female unvaccinated and seronegative recruits studied longitudinally, SARS-CoV-2 infections occurred in 1,033 males and 137 females. We identified sex differences in symptoms, viral load, blood transcriptome, RNA splicing, and proteomic signatures. Females had higher pre-infection expression of antiviral interferon-stimulated gene (ISG) programs. Causal mediation analysis implicated ISG differences in number of symptoms, levels of ISGs, and differential splicing of CD45 lymphocyte phosphatase during infection. Our results indicate that the antiviral innate immunity set point causally contributes to sex differences in response to SARS-CoV-2 infection. A record of this paper’s transparent peer review process is included in the supplemental information.

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November 1, 2022

Nested R: Assessing the convergence of Markov chains Monte Carlo when running many short chains

Recent developments in Markov chain Monte Carlo (MCMC) algorithms now allow us to run thousands of chains in parallel almost as quickly as a single chain, using hardware accelerators such as GPUs. We explore the benefits of running many chains, with an emphasis on achieving a target precision in as short a time as possible. One expected advantage is that, while each chain still needs to forget its initial point during a warmup phase, the subsequent sampling phase can be almost arbitrarily short. To determine if the resulting short chains are reliable, we need to assess how close the Markov chains are to convergence to their stationary distribution. The R̂ statistic is a general purpose and popular convergence diagnostic but unfortunately can require a long sampling phase to work well. We present a nested design to overcome this challenge and a generalization called nested R̂ . This new diagnostic works under conditions similar to R̂ and completes the MCMC workflow for many GPU-friendly samplers. In addition, the proposed nesting provides theoretical insights into the utility of R̂ , in both classical and short-chains regimes.

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November 1, 2022

Adaptive Tuning for Metropolis Adjusted Langevin Trajectories

Hamiltonian Monte Carlo (HMC) is a widely used sampler for continuous probability distributions. In many cases, the underlying Hamiltonian dynamics exhibit a phenomenon of resonance which decreases the efficiency of the algorithm and makes it very sensitive to hyperparameter values. This issue can be tackled efficiently, either via the use of trajectory length randomization (RHMC) or via partial momentum refreshment. The second approach is connected to the kinetic Langevin diffusion, and has been mostly investigated through the use of Generalized HMC (GHMC). However, GHMC induces momentum flips upon rejections causing the sampler to backtrack and waste computational resources. In this work we focus on a recent algorithm bypassing this issue, named Metropolis Adjusted Langevin Trajectories (MALT). We build upon recent strategies for tuning the hyperparameters of RHMC which target a bound on the Effective Sample Size (ESS) and adapt it to MALT, thereby enabling the first user-friendly deployment of this algorithm. We construct a method to optimize a sharper bound on the ESS and reduce the estimator variance. Easily compatible with parallel implementation, the resultant Adaptive MALT algorithm is competitive in terms of ESS rate and hits useful tradeoffs in memory usage when compared to GHMC, RHMC and NUTS.

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October 21, 2022

Multibody molecular docking on a quantum annealer

Mohit Pandey, Tristan Zaborniak, V. Mulligan, et al

Molecular docking, which aims to find the most stable interacting configuration of a set of molecules, is of critical importance to drug discovery. Although a considerable number of classical algorithms have been developed to carry out molecular docking, most focus on the limiting case of docking two molecules. Since the number of possible configurations of N molecules is exponential in N, those exceptions which permit docking of more than two molecules scale poorly, requiring exponential resources to find high-quality solutions. Here, we introduce a one-hot encoded quadratic unconstrained binary optimization formulation (QUBO) of the multibody molecular docking problem, which is suitable for solution by quantum annealer. Our approach involves a classical pre-computation of pairwise interactions, which scales only quadratically in the number of bodies while permitting well-vetted scoring functions like the Rosetta REF2015 energy function to be used. In a second step, we use the quantum annealer to sample low-energy docked configurations efficiently, considering all possible docked configurations simultaneously through quantum superposition. We show that we are able to minimize the time needed to find diverse low-energy docked configurations by tuning the strength of the penalty used to enforce the one-hot encoding, demonstrating a 3-4 fold improvement in solution quality and diversity over performance achieved with conventional penalty strengths. By mapping the configurational search to a form compatible with current- and future-generation quantum annealers, this work provides an alternative means of solving multibody docking problems that may prove to have performance advantages for large problems, potentially circumventing the exponential scaling of classical approaches and permitting a much more efficient solution to a problem central to drug discovery and validation pipelines.

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