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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 145 records · Page 8
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Assembly of JAZ–JAZ and JAZ–NINJA complexes in jasmonate signaling

Jasmonates (JAs) are plant hormones with crucial roles in development and stress resilience. They activate MYC transcription factors by mediating the proteolysis of MYC inhibitors called JAZ proteins. In the absence of JA, JAZ proteins bind and inhibit MYC through the assembly of MYC–JAZ–Novel Interactor of JAZ (NINJA)–TPL repressor complexes. However, JAZ and NINJA are predicted to be largely intrinsically unstructured, which has precluded their experimental structure determination. Through a combination of biochemical, mutational, and biophysical analyses and AlphaFold-derived ColabFold modeling, we characterized JAZ–JAZ and JAZ–NINJA interactions and generated models with detailed, high-confidence domain interfaces. We demonstrate that JAZ, NINJA, and MYC interface domains are dynamic in isolation and become stabilized in a stepwise order upon complex assembly. By contrast, most JAZ and NINJA regions outside of the interfaces remain highly dynamic and cannot be modeled in a single conformation. Our data indicate that the small JAZ Zinc finger expressed in Inflorescence Meristem (ZIM) motif mediates JAZ–JAZ and JAZ–NINJA interactions through separate surfaces, and our data further suggest that NINJA modulates JAZ dimerization. This study advances our understanding of JA signaling by providing insights into the dynamics, interactions, and structure of the JAZ–NINJA core of the JA repressor complex.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Dynamic Profiling of β-Coronavirus 3CL Mpro Protease Ligand-Binding Sites

β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensable role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand–protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV Mpro. Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-CoV homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

mphys-surrogate-model

This repository contains python scripts for building and studying reduced-order-modeling representations of droplet coalescence for eventual use in atmospheric models. The included data are generated from high-fidelity superdroplet methods and are utilized by machine learning pipelines to build data-driven models of droplet size distributions that evolve under coalescence. This repository further includes scripts to determine prediction (uncertainty) intervals on the data-driven model products based on conformal prediction.

Katona, JonasE [Lawrence Livermore National Labora↗
DOE OSTI2024

Correcting implicit solvation at metal/water interfaces through the incorporation of competitive water adsorption

Conventional continuum solvation models are ubiquitous in computational catalysis, including for describing metal/water interfaces, which are relevant to both solution-phase heterogeneous catalysis and electrocatalysis. Nonetheless, we find that such continuum models qualitatively fail to describe both the adsorption free energy and conformational preference for many organic molecules at such interfaces, largely due to the failure of continuum models to incorporate the role of competitive water adsorption. We develop a simple phenomenological model that accounts for competitive water adsorption and show that the model, when used in conjunction with continuum solvation, provides a dramatic improvement in the description of both adsorption and conformational preference. The model is also extended to additionally incorporate the influence of applied potential at the electrode surface, thus facilitating computationally efficient applications to scenarios including electrocatalysis.

Chemistry↗
DOE OSTI2020

Modeling of Hidden Structures Using Sparse Chemical Shift Data from NMR Relaxation Dispersion

NMR relaxation dispersion measurements report on conformational changes occurring on the μs-ms timescale. Chemical shift information derived from relaxation dispersion can be used to generate structural models of weakly populated alternative conformational states. Current methods to obtain such models rely on determining the signs of chemical shift changes between the conformational states, which are difficult to obtain in many situations. Here, we use a “sample and select” method to generate relevant structural models of alternative conformations of the C-terminal-associated region of Escherichia coli dihydrofolate reductase (DHFR), using only unsigned chemical shift changes for backbone amides and carbonyls ( 1 H, 15 N, and 13 C'). We find that CS-Rosetta sampling with unsigned chemical shift changes generates a diversity of structures that are sufficient to characterize a minor conformational state of the C-terminal region of DHFR. The excited state differs from the ground state by a change in secondary structure, consistent with previous predictions from chemical shift hypersurfaces and validated by the x-ray structure of a partially humanized mutant of E. coli DHFR (N23PP/G51PEKN). The results demonstrate that the combination of fragment modeling with sparse chemical shift data can determine the structure of an alternative conformation of DHFR sampled on the μs-ms timescale. Such methods will be useful for characterizing alternative states, which can potentially be used for in silico drug screening, as well as contributing to understanding the role of minor states in biology and molecular evolution.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Hydration Free Energies of Polypeptides from Popular Implicit Solvent Models versus All-Atom Simulation Results Based on Molecular Quasichemical Theory

Calculating the hydration free energy of a macromolecule in all-atom simulations has long remained a challenge, necessitating the use of models wherein the effect of the solvent is captured without explicit account of solvent degrees of freedom. This situation has changed with developments in the molecular quasi-chemical theory (QCT)-an approach that enables calculation of the hydration free energy of macromolecules within all-atom simulations at the same resolution as is possible for small molecular solutes. The theory also provides a rigorous and physically transparent framework to conceptualize and model interactions in molecular solutions and thus provides a convenient framework to investigate the assumptions in implicit solvent models. In this study, we compare the results using molecular QCT versus predictions from EEF1, ABSINTH, and GB/SA implicit solvent models for polyglycine and polyalanine solutes covering a range of chain lengths and conformations. The hydration free energies or the differences in hydration free energies between conformers obtained from the implicit solvent models do not agree with explicit solvent results, with the deviations being largest for the group additive EEF1 and ABSINTH models. GB/SA does better in capturing the qualitative trends seen in explicit solvent results. Finally, analysis founded on QCT reveals the critical importance of the cooperativity of hydration that is inherent in the hydrophilic and hydrophobic contributions to hydration-physics that is not well captured in additive models but somewhat better accounted for by means of a dielectric in the GB/SA approach.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Anisotropic Coarse-Grained Model for Conjugated Polymers: Investigations into Solution Morphologies

The optoelectronic properties of conjugated polymers are dictated by the interplay of multiscale structural features, including intrachain dihedrals, interchain pi-pi stacking, and the complex mesoscale morphology. While much is known about the structures of polymers with isotropically interacting monomers, little is known about polymers with strongly anisotropic backbone monomers, a class of materials to which conjugated polymers belong. Fundamental understanding is further complicated when the semiflexible and molecularly heterogeneous nature of conjugated polymers is taken into account. We present an anisotropic coarse-grained (CG) model for conjugated polymers that incorporates key molecular features (monomer anisotropy, intermonomer dihedrals, and side chains). Finally, the model is employed to characterize the single-chain conformational properties of conjugated polymers, revealing a rich temperature-dependent conformational landscape. These studies provide a critical link between CG molecular descriptors and conformational ordering in conjugated polymers.

36 MATERIALS SCIENCE↗
DOE OSTI2026

The Molecular Structures of Liquid and Glassy Nifedipine and Felodipine and Their Incorporation into PVP

Background: Amorphous drug formulations are commonly used to improve the solubility and bioavailability of poorly soluble molecular pharmaceuticals, yet less is known about their molecular conformations and local bonding interactions than their crystalline phases. Methods: High-energy X-ray diffraction structure factor measurements have been made on liquid and glassy nifedipine (NIF), felodipine (FEL), NIF 1:3 polyvinylpyrrolidone (PVP), and FEL 1:3 PVP wt.% mixtures. The corresponding X-ray pair distribution functions have been interpreted using empirical potential structure refinement using different models and density functional theory conformer calculations. Results: In both NIF and FEL, the NH···O inter-molecular hydrogen bonds between the pyridyl nitrogen and ester carbonyls are found to be considerably weaker than those observed in the crystalline polymorphs. For nifedipine, it is proposed that either inter-molecular NH…ON nitro bonds are present and/or a fraction (<20%) of conformational changes, with the aryl ring flipped, occur in the liquid state. For felodipine, the models indicate significant disorder associated with the methyl and ethyl side chains in the liquid state, with the main peak intensity at 3.0 Å arising from intra-molecular Cl-Cl atom pairs. When nifedipine molecules are incorporated into PVP, our models show they possess stronger NH···O bonds to the PVP polymer than felodipine molecules, which have stronger affinity for bonding to the polymer than to other felodipine molecules. Conclusions: The amorphous forms of both NIF and FEL show much weaker hydrogen bonding than found in their crystalline phases. Liquid NIF also exhibits configurations which are not observed in the crystal phases.

Amorphous Solid Dispersion↗
DOE OSTI2023

GRB2 dimerization mediated by SH2 domain-swapping is critical for T cell signaling and cytokine production

GRB2 is an adaptor protein required for facilitating cytoplasmic signaling complexes from a wide array of binding partners. GRB2 has been reported to exist in either a monomeric or dimeric state in crystal and solution. GRB2 dimers are formed by the exchange of protein segments between domains, otherwise known as “domain-swapping”. Swapping has been described between SH2 and C-terminal SH3 domains in the full-length structure of GRB2 (SH2/C–SH3 domain-swapped dimer), as well as between α-helixes in isolated GRB2 SH2 domains (SH2/SH2 domain-swapped dimer). Interestingly, SH2/SH2 domain-swapping has not been observed within the full-length protein, nor have the functional influences of this novel oligomeric conformation been explored. We herein generated a model of full-length GRB2 dimer with an SH2/SH2 domain-swapped conformation supported by in-line SEC–MALS–SAXS analyses. This conformation is consistent with the previously reported truncated GRB2 SH2/SH2 domain-swapped dimer but different from the previously reported, full-length SH2/C-terminal SH3 (C–SH3) domain-swapped dimer. Our model is also validated by several novel full-length GRB2 mutants that favor either a monomeric or a dimeric state through mutations within the SH2 domain that abrogate or promote SH2/SH2 domain-swapping. GRB2 knockdown and re-expression of selected monomeric and dimeric mutants in a T cell lymphoma cell line led to notable defects in clustering of the adaptor protein LAT and IL-2 release in response to TCR stimulation. These results mirrored similarly-impaired IL-2 release in GRB2-deficient cells. These studies show that a novel dimeric GRB2 conformation with domain-swapping between SH2 domains and monomer/dimer transitions are critical for GRB2 to facilitate early signaling complexes in human T cells.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Integrated structural model of the palladin–actin complex using XL ‐ MS , docking, NMR , and SAXS

Abstract Palladin is an actin‐binding protein that accelerates actin polymerization and is linked to the metastasis of several types of cancer. Previously, three lysine residues in an immunoglobulin‐like domain of palladin have been identified as essential for actin binding. However, it is still unknown where palladin binds to F‐actin. Evidence that palladin binds to the sides of actin filaments to facilitate branching is supported by our previous study showing that palladin was able to compensate for Arp2/3 in the formation of Listeria actin comet tails. Here, we used chemical crosslinking to covalently link palladin and F‐actin residues based on spatial proximity. Samples were then enzymatically digested, separated by liquid chromatography, and analyzed by tandem mass spectrometry. Peptides containing the crosslinks and specific residues involved were then identified for input to the HADDOCK docking server to model the most likely binding conformation. Small‐angle x‐ray scattering was used to provide further insight into palladin flexibility and the binding interface, and NMR spectra identified potential interactions between palladin's Ig domains. Our final structural model of the F‐actin:palladin complex revealed how palladin interacts with and stabilizes F‐actin at the interface between two actin monomers. Three actin residues that were identified in this study also appear commonly in the actin‐binding interface with other proteins such as myotilin, myosin, and tropomodulin. An accurate structural representation of the complex between palladin and actin extends our understanding of palladin's role in promoting cancer metastasis through the regulation of actin dynamics.

Sargent, Rachel [Department of Chemistry and Bioch↗
DOE OSTI2021

Structures of the ApoL1 and ApoL2 N-terminal domains reveal a non-classical four-helix bundle motif

Apolipoprotein L1 (ApoL1) is a circulating innate immunity protein protecting against trypanosome infection. However, two ApoL1 coding variants are associated with a highly increased risk of chronic kidney disease. Here we present X-ray and NMR structures of the N-terminal domain (NTD) of ApoL1 and of its closest relative ApoL2. In both proteins, four of the five NTD helices form a four-helix core structure which is different from the classical four-helix bundle and from the pore-forming domain of colicin A. The reactivity with a conformation-specific antibody and structural models predict that this four-helix motif is also present in the NTDs of ApoL3 and ApoL4, suggesting related functions within the small ApoL family. The long helix 5 of ApoL1 is conformationally flexible and contains the BH3-like region. This BH3-like α-helix resembles true BH3 domains only in sequence and structure but not in function, since it does not bind to the pro-survival members of the Bcl-2 family, suggesting a Bcl-2-independent role in cytotoxicity. These findings should expedite a more comprehensive structural and functional understanding of the ApoL immune protein family.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Atomic protein structure refinement using all-atom graph representations and SE(3)-equivariant graph transformer

Abstract Motivation The state-of-art protein structure prediction methods such as AlphaFold are being widely used to predict structures of uncharacterized proteins in biomedical research. There is a significant need to further improve the quality and nativeness of the predicted structures to enhance their usability. In this work, we develop ATOMRefine, a deep learning-based, end-to-end, all-atom protein structural model refinement method. It uses a SE(3)-equivariant graph transformer network to directly refine protein atomic coordinates in a predicted tertiary structure represented as a molecular graph. Results The method is first trained and tested on the structural models in AlphaFoldDB whose experimental structures are known, and then blindly tested on 69 CASP14 regular targets and 7 CASP14 refinement targets. ATOMRefine improves the quality of both backbone atoms and all-atom conformation of the initial structural models generated by AlphaFold. It also performs better than two state-of-the-art refinement methods in multiple evaluation metrics including an all-atom model quality score—the MolProbity score based on the analysis of all-atom contacts, bond length, atom clashes, torsion angles, and side-chain rotamers. As ATOMRefine can refine a protein structure quickly, it provides a viable, fast solution for improving protein geometry and fixing structural errors of predicted structures through direct coordinate refinement. Availability and implementation The source code of ATOMRefine is available in the GitHub repository (https://github.com/BioinfoMachineLearning/ATOMRefine). All the required data for training and testing are available at https://doi.org/10.5281/zenodo.6944368.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Graphical Gaussian Process Regression Model for Aqueous Solvation Free Energy Prediction of Organic Molecules in Redox Flow Battery

The solvation free energy of organic molecules is a critical parameter in determining emergent properties such as solubility, liquid-phase equilibrium constants, and pKa and redox potentials in an organic redox flow battery. In this work, we present a machine learning (ML) model that can learn and predict the aqueous solvation free energy of an organic molecule using Gaussian process regression method based on a new molecular graph kernel. To investigate the performance of the ML model on electrostatic interaction, the nonpolar interaction contribution of solvent and the conformational entropy of solute in solvation free energy, three data sets with implicit or explicit water solvent models, and contribution of conformational entropy of solute are tested. We demonstrate that our ML model can predict the solvation free energy of molecules at chemical accuracy with a mean absolute error of less than 1 kcal/mol for subsets of the QM9 dataset and the Freesolv database. To solve the general data scarcity problem for a graph-based ML model, we propose a dimension reduction algorithm based on the distance between molecular graphs, which can be used to examine the diversity of the molecular data set. It provides a promising way to build a minimum training set to improve prediction for certain test sets where the space of molecular structures is predetermined.

25 ENERGY STORAGE↗
DOE OSTI2023

Comparative Study of High-Resolution LysB29(Nε-myristoyl) des(B30) Insulin Structures Display Novel Dynamic Causal Interrelations in Monomeric-Dimeric Motions

The treatment of insulin-dependent diabetes mellitus is characterized by artificial supplementation of pancreatic β-cell ability to regulate sugar levels in the blood. Even though various insulin analogs are crucial for reasonable glycemic control, understanding the dynamic mechanism of the insulin analogs may help to improve the best-protracted insulin analog to assist people with type 1 diabetes (T1D) to live comfortably while maintaining tight glycemic control. Here, we present the high-resolution crystal structure of NN304, known as insulin detemir, to 1.7 Å resolution at cryogenic temperature. We computationally further investigated our crystal structure’s monomeric-dimeric conformation and dynamic profile by comparing it with a previously available detemir structure (PDB ID: 1XDA). Our structure (PDB ID: 8HGZ), obtained at elevated pH, provides electrostatically triggered minor movements in the equilibrium between alternate conformational substates compared to the previous structure, suggesting it might induce an intermediate state in the dissociation pathway of the insulin detemir’s hexamer:dihexamer equilibrium. Supplemented with orientational cross-correlation analysis by a Gaussian network model (GNM), this alternate oligomeric conformation offers the distinct cooperative motions originated by loose coupling of distant conformational substates of a protracted insulin analog that has not been previously observed.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Missing components in ΛCDM from DESI Y1 baryonic acoustic oscillation measurements: Insights from redshift remapping

We explore transformations of the Friedman-Lemaître-Robertson-Walker (FLRW) metric and cosmological parameters that align with observational data while aiming to gain insights into potential extensions of standard cosmological models. We modified the FLRW metric by introducing a scaling factor, e 2Θ(a) –the cosmological scaling function (CSF), which alters the standard relationship between cosmological redshift and the cosmic scale factor without affecting angular measurements or cosmic microwave background (CMB) anisotropies. Using data from DESI Year 1, Pantheon+ supernovae, and the Planck CMB temperature power spectrum, we constrained both the CSF and cosmological parameters through a Markov chain Monte Carlo approach. Our results indicate that the CSF model fits observational data with a lower Hubble constant (although it is compatible with the value given by Planck 2018 within 1σ) and is predominantly dark matter dominated. Additionally, the CSF model produces temperature and lensing power spectra similar to those predicted by the standard model, though with lower values in the CSF model at large scales. We also checked that when fitting a CSF model without dark energy to the data, we obtain a more negative conformal function. This suggests that the CSF model may offer hints about missing elements and opens up a new avenue for exploring physical interpretations of cosmic acceleration.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2022

Counterions under a Surface-Adsorbed Cationic Surfactant Monolayer: Structure and Thermodynamics

The surface adsorption of ionic surfactants is fundamental for many widespread phenomena in life sciences and for a wide range of technological applications. However, direct atomic-resolution structural experimental studies of noncrystalline surface-adsorbed films are scarce. Thus, even the most central physical aspects of these films, such as their charge density, remain uncertain. Consequently, theoretical models based on contradicting assumptions as for the surface films' ionization are widely used for the description and prediction of surface thermodynamics. We employ X-ray reflectivity to obtain the angstrom Ångström-scale surface-normal structure of surface-adsorbed films of the cationic surfactant cetyltrimethylammonium bromide (CTAB) in aqueous solutions at several different temperatures and concentrations. In conjunction with published neutron reflectivity data, we determine the surface-normal charge distribution due to the dissociated surfactants' headgroups. The distribution appears to be inconsistent with the Gouy-Chapman model yet consistent with a compact Stern layer model of condensed counterions. Here, the experimental surfactant adsorption thermodynamics conforms well to classical, Langmuir and Kralchevsky, adsorption models. Furthermore, the Kralchevsky model correctly reproduces the observed condensation of counterions, allowing the values of the adsorption parameters to be resolved, based on the combination of the present data and the published surface tension measurements.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Understanding Viscoelasticity of an Entangled Silicone Copolymer via Coarse-Grained Molecular Dynamics Simulations

Entangled dynamics is important for understanding rheological properties of long-chain polymers. For entangled homopolymers, the classic tube-reptation model and its refinements have been successfully applied to quantify properties like diffusion coefficient and zero-rate viscosity. However, the application of such models to copolymers has been limited despite scientific and industrial importance. Here, we study the entangled melt dynamics of poly(dimethyl-co-diphenyl)siloxane random copolymer for a range of mean-composition-ratio ϕ of the diphenyl component via long-term molecular dynamics simulation with a recently developed coarse-grained model. We found that the segmental relaxation is heterogeneous at the monomeric level because of compositional fluctuations. However, at the chain-entanglement level and higher length scales, the viscoelastic response is homogeneous with compositional dependence only through the overall diphenyl fraction ϕ. The relaxation modulus of the entangled copolymer melt conforms to the Likhtman–McLeish model, and the viscosity predicted using our current coarse-grained parameters is in good quantitative agreement with experimental data.

Copolymers↗
DOE OSTI2022

Ensemble-function relationships to dissect mechanisms of enzyme catalysis

Decades of structure-function studies have established our current extensive understanding of enzymes. However, traditional structural models are snapshots of broader conformational ensembles of interchanging states. We demonstrate the need for conformational ensembles to understand function, using the enzyme ketosteroid isomerase (KSI) as an example. Comparison of prior KSI cryogenic x-ray structures suggested deleterious mutational effects from a misaligned oxyanion hole catalytic residue. However, ensemble information from room-temperature x-ray crystallography, combined with functional studies, excluded this model. Ensemble-function analyses can deconvolute effects from altering the probability of occupying a state (P-effects) and changing the reactivity of each state (k-effects); our ensemble-function analyses revealed functional effects arising from weakened oxyanion hole hydrogen bonding and substrate repositioning within the active site. Ensemble-function studies will have an integral role in understanding enzymes and in meeting the future goals of a predictive understanding of enzyme catalysis and engineering new enzymes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗