2,205 research outputs found
DiAMoNDBack: Diffusion-denoising Autoregressive Model for Non-Deterministic Backmapping of C{\alpha} Protein Traces
Coarse-grained molecular models of proteins permit access to length and time
scales unattainable by all-atom models and the simulation of processes that
occur on long-time scales such as aggregation and folding. The reduced
resolution realizes computational accelerations but an atomistic representation
can be vital for a complete understanding of mechanistic details. Backmapping
is the process of restoring all-atom resolution to coarse-grained molecular
models. In this work, we report DiAMoNDBack (Diffusion-denoising Autoregressive
Model for Non-Deterministic Backmapping) as an autoregressive denoising
diffusion probability model to restore all-atom details to coarse-grained
protein representations retaining only C{\alpha} coordinates. The
autoregressive generation process proceeds from the protein N-terminus to
C-terminus in a residue-by-residue fashion conditioned on the C{\alpha} trace
and previously backmapped backbone and side chain atoms within the local
neighborhood. The local and autoregressive nature of our model makes it
transferable between proteins. The stochastic nature of the denoising diffusion
process means that the model generates a realistic ensemble of backbone and
side chain all-atom configurations consistent with the coarse-grained C{\alpha}
trace. We train DiAMoNDBack over 65k+ structures from Protein Data Bank (PDB)
and validate it in applications to a hold-out PDB test set,
intrinsically-disordered protein structures from the Protein Ensemble Database
(PED), molecular dynamics simulations of fast-folding mini-proteins from DE
Shaw Research, and coarse-grained simulation data. We achieve state-of-the-art
reconstruction performance in terms of correct bond formation, avoidance of
side chain clashes, and diversity of the generated side chain configurational
states. We make DiAMoNDBack model publicly available as a free and open source
Python package
Understanding How Kurtosis Is Transferred from Input Acceleration to Stress Response and Its Influence on Fatigue Llife
High cycle fatigue of metals typically occurs through long term exposure to time varying loads which, although modest in amplitude, give rise to microscopic cracks that can ultimately propagate to failure. The fatigue life of a component is primarily dependent on the stress amplitude response at critical failure locations. For most vibration tests, it is common to assume a Gaussian distribution of both the input acceleration and stress response. In real life, however, it is common to experience non-Gaussian acceleration input, and this can cause the response to be non-Gaussian. Examples of non-Gaussian loads include road irregularities such as potholes in the automotive world or turbulent boundary layer pressure fluctuations for the aerospace sector or more generally wind, wave or high amplitude acoustic loads. The paper first reviews some of the methods used to generate non-Gaussian excitation signals with a given power spectral density and kurtosis. The kurtosis of the response is examined once the signal is passed through a linear time invariant system. Finally an algorithm is presented that determines the output kurtosis based upon the input kurtosis, the input power spectral density and the frequency response function of the system. The algorithm is validated using numerical simulations. Direct applications of these results include improved fatigue life estimations and a method to accelerate shaker tests by generating high kurtosis, non-Gaussian drive signals
Permutationally Invariant Networks for Enhanced Sampling (PINES): Discovery of Multi-Molecular and Solvent-Inclusive Collective Variables
The typically rugged nature of molecular free energy landscapes can frustrate
efficient sampling of the thermodynamically relevant phase space due to the
presence of high free energy barriers. Enhanced sampling techniques can improve
phase space exploration by accelerating sampling along particular collective
variables (CVs). A number of techniques exist for data-driven discovery of CVs
parameterizing the important large scale motions of the system. A challenge to
CV discovery is learning CVs invariant to symmetries of the molecular system,
frequently rigid translation, rigid rotation, and permutational relabeling of
identical particles. Of these, permutational invariance have proved a
persistent challenge in frustrating the the data-driven discovery of
multi-molecular CVs in systems of self-assembling particles and
solvent-inclusive CVs for solvated systems. In this work, we integrate
Permutation Invariant Vector (PIV) featurizations with autoencoding neural
networks to learn nonlinear CVs invariant to translation, rotation, and
permutation, and perform interleaved rounds of CV discovery and enhanced
sampling to iteratively expand sampling of configurational phase space and
obtain converged CVs and free energy landscapes. We demonstrate the
Permutationally Invariant Network for Enhanced Sampling (PINES) approach in
applications to the self-assembly of a 13-atom Argon cluster,
association/dissociation of a NaCl ion pair in water, and hydrophobic collapse
of a C45H92 n-pentatetracontane polymer chain. We make the approach freely
available as a new module within the PLUMED2 enhanced sampling libraries
Avirulent Strains of Toxoplasma Gondii Infect Macrophages by Active Invasion from the Phagosome
Unlike most intracellular pathogens that gain access into host cells through endocytic pathways, Toxoplasma gondii initiates infection at the cell surface by active penetration through a moving junction and subsequent formation of a parasitophorous vacuole. Here, we describe a noncanonical pathway for T. gondii infection of macrophages, in which parasites are initially internalized through phagocytosis, and then actively invade from within a phagosomal compartment to form a parasitophorous vacuole. This phagosome to vacuole invasion (PTVI) pathway may represent an intermediary link between the endocytic and the penetrative routes for host cell entry by intracellular pathogens. The PTVI pathway is preferentially used by avirulent strains of T. gondii and confers an infectious advantage over virulent strains for macrophage tropism
A hybrid double-dot in silicon
We report electrical measurements of a single arsenic dopant atom in the
tunnel-barrier of a silicon SET. As well as performing electrical
characterization of the individual dopant, we study series electrical transport
through the dopant and SET. We measure the triple points of this hybrid double
dot, using simulations to support our results, and show that we can tune the
electrostatic coupling between the two sub-systems.Comment: 11 pages, 6 figure
HST and Palomar Imaging of GRB 990123: Implications for the Nature of Gamma-Ray Bursts and their Hosts
We report on HST and Palomar optical images of the field of GRB 990123,
obtained on 8 and 9 February 1999. We find that the optical transient (OT)
associated with GRB 990123 is located on an irregular galaxy, with magnitude
V=24.20 +/- 0.15. The strong metal absorption lines seen in the spectrum of the
OT, along with the low probability of a chance superposition, lead us to
conclude that this galaxy is the host of the GRB. The OT is projected within
the ~1'' visible stellar field of the host, nearer the edge than the center. We
cannot, on this basis, rule out the galactic nucleus as the site of the GRB,
since the unusual morphology of the host may be the result of an ongoing
galactic merger, but our demonstration that this host galaxy has extremely blue
optical to infrared colors more strongly supports an association between GRBs
and star formation. We find that the OT magnitude on 1999 Feb 9.05, V = 25.45
+/- 0.15, is about 1.5 mag fainter than expected from extrapolation of the
decay rate found in earlier observations. A detailed analysis of the OT light
curve suggests that its fading has gone through three distinct phases: an early
rapid decline (f_{nu} \propto t^{-1.6} for t < 0.1 days), a slower intermediate
decline power-law decay (f_{nu} \propto t^{-1.1} for 0.1 < t < 2 days), and
then a more rapid decay (at least as steep as (f_{\nu} \propto t^{-1.8} for t >
2 days). The break to steeper slope at late times may provide evidence that the
optical emission from this GRB was highly beamed.Comment: Accepted for publication in Astrophysical Journal (Letters). Fourteen
pages. Three encapsulated figure
Computational Prediction of Broadly Neutralizing HIV-1 Antibody Epitopes from Neutralization Activity Data
Broadly neutralizing monoclonal antibodies effective against the majority of circulating isolates of HIV-1 have been isolated from a small number of infected individuals. Definition of the conformational epitopes on the HIV spike to which these antibodies bind is of great value in defining targets for vaccine and drug design. Drawing on techniques from compressed sensing and information theory, we developed a computational methodology to predict key residues constituting the conformational epitopes on the viral spike from cross-clade neutralization activity data. Our approach does not require the availability of structural information for either the antibody or antigen. Predictions of the conformational epitopes of ten broadly neutralizing HIV-1 antibodies are shown to be in good agreement with new and existing experimental data. Our findings suggest that our approach offers a means to accelerate epitope identification for diverse pathogenic antigens
Effects of red meat or iron-fortified milk on iron status of 12–20 month old New Zealand (NZ) children : a randomized controlled trial
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