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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 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Novel fold of rotavirus glycan-binding domain predicted by AlphaFold2 and determined by X-ray crystallography

The VP8* domain of spike protein VP4 in group A and C rotaviruses, which cause epidemic gastroenteritis in children, exhibits a conserved galectin-like fold for recognizing glycans during cell entry. In group B rotavirus, which causes significant diarrheal outbreaks in adults, the VP8* domain (VP8*B) surprisingly lacks sequence similarity with VP8* of group A or group C rotavirus. Here, by using the recently developed AlphaFold2 for ab initio structure prediction and validating the predicted model by determining a 1.3-Å crystal structure, we show that VP8*B exhibits a novel fold distinct from the galectin fold. This fold with a β-sheet clasping an α-helix represents a new fold for glycan recognition based on glycan array screening, which shows that VP8*B recognizes glycans containing N-acetyllactosamine moiety. Although uncommon, our study illustrates how evolution can incorporate structurally distinct folds with similar functionality in a homologous protein within the same virus genus.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Folding Coarse-Grained Oligomer Models with PyRosetta

Non-biological foldamers are a promising class of macromolecules that share similarities to classical biopolymers such as proteins and nucleic acids. Currently, designing novel foldamers is a non-trivial process, often involving many iterations of trial synthesis and characterization until folded structures are observed. In this work, we aim to tackle these foldamer design challenges using computational modeling techniques. We developed CG PyRosetta, an extension to the popular protein folding python package, PyRosetta, which introduces coarse-grained (CG) residues into PyRosetta, enabling the folding of toy CG foldamer models. Although these models are simplified, they can help explore overarching physical hypotheses about how oligomers can form. Through systematic variation of CG parameters in these models, we can investigate various folding hypotheses at the CG scale to inform the design process of new foldamer chemistries. In this study, we demonstrate CG PyRosetta’s ability to identify minimum energy structures with a diverse structural search over a range of simple models, as well as two hypothesis-driven parameter scans investigating the effects of side-chain size and internal backbone angle on secondary structures. We are able to identify several types of secondary structures from single- and double-helices to sheet-like and knot-like structures. Here, we show how side-chain size and backbone bond angle both play an important role in the structure and energetics of these toy models. Optimal side-chain sizes promote favorable packing of side chains, while specific backbone bond angles influence the specific helix type found in folded structures.

36 MATERIALS SCIENCE↗
DOE OSTI2022

Electric-field control of the nucleation and motion of isolated three-fold polar vertices

Recently various topological polar structures have been discovered in oxide thin films. Despite the increasing evidence of their switchability under electrical and/or mechanical fields, the dynamic property of isolated ones, which is usually required for applications such as data storage, is still absent. Here, we show the controlled nucleation and motion of isolated three-fold vertices under an applied electric field. At the PbTiO 3 /SrRuO 3 interface, a two-unit-cell thick SrTiO 3 layer provides electrical boundary conditions for the formation of three-fold vertices. Utilizing the SrTiO 3 layer and in situ electrical testing system, we find that isolated three-fold vertices can move in a controllable and reversible manner with a velocity up to ~629 nm s -1 . Microstructural evolution of the nucleation and propagation of isolated three-fold vertices is further revealed by phase-field simulations. This work demonstrates the ability to electrically manipulate isolated three-fold vertices, shedding light on the dynamic property of isolated topological polar structures.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2025

Carbon Storage in Fold‐and‐Thrust Belts: An Overlooked Gigatonne Storage Opportunity

This study presents numerical investigations of the trapping characteristics of fold-and-thrust belt structures, defining three carbon capture and storage (CCS) play types that could be used to store commercial volumes (millions of tonnes) of CO 2 . Specifically, we present simulations of CO 2 storage in three fold-and-thrust belt models comprising a thrust-ramp, duplex, and thrust-fold geometry. To constrain these play types in realistic geology, each model is based on a study site, including a novel investigation of a greenfield saline reservoir in Virginia, USA, being considered for commercial carbon storage and two well-characterized petroleum fields: the Wilburton field in Oklahoma, USA, and the Incahuasi field in Bolivia. Our results provide insight into several key parameters, such as the long-term security of injected CO 2 in these geologies and injection strategies for maximizing storage efficiency while reducing pressure-related risk. These results improve the understanding of CCS in fold-and-thrust belt storage sites globally by describing general storage parameters that may be applied to site-specific projects. We find that thrust-ramp geometries may securely trap CO 2 through solubility and hydrodynamic trapping under suitable reservoir conditions, duplex structures may store some quantities of CO 2 but are pressure-constrained, and that thrust-ramp structures may store large quantities of CO 2 by maximizing fetch volume, which simultaneously lowers geomechanical risk by reducing pressure buildup along zones of weakness.

42 ENGINEERING↗
DOE OSTI2021

Atomistic Mechanics of Torn Back Folded Edges of Triangular Voids in Monolayer WS 2

Triangular nanovoids in 2D materials transition metal dichalcogenides have vertex points that cause stress concentration and lead to sharp crack propagation and failure. Here, the atomistic mechanics of back folding around triangular nanovoids in monolayer WS 2 sheets is examined. Combining atomic-resolution images from annular dark-field scanning transmission electron microscopy with reactive molecular modelling, it is revealed that the folding edge formation has statistical preferences under geometric conditions based on the orientation mismatch. It is further investigated how loading directions and strong interlayer friction, interplay with WS 2 lattice's crack preference, govern the deformation and fracture pattern around folding edges. Finally, these results provide fundamental insights into the combination of fracture and folding in flexible monolayer crystals and the resultant Moiré lattices.

36 MATERIALS SCIENCE↗
DOE OSTI2023

Structural and dynamic mechanisms for coupled folding and tRNA recognition of a translational T-box riboswitch

T-box riboswitches are unique riboregulators where gene regulation is mediated through interactions between two highly structured RNAs. Despite extensive structural insights, how RNA-RNA interactions drive the folding and structural transitions of T-box to achieve functional conformations remains unclear. Here, by combining SAXS, single-molecule FRET and computational modeling, we elaborate the folding energy landscape of a translational T-box aptamer consisting of stems I, II and IIA/B, which Mg 2+ -induced global folding and tRNA binding are cooperatively coupled. smFRET measurements reveal that high Mg 2+ stabilizes IIA/B and its stacking on II, which drives the pre-docking of I and II into a competent conformation, subsequent tRNA binding promotes docking of I and II to form a high-affinity tRNA binding groove, of which the essentiality of IIA/B and S-turn in II is substantiated with mutational analysis. We highlight a delicate balance among Mg 2+ , the intra- and intermolecular RNA-RNA interactions in modulating RNA folding and function.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Structural basis of tRNA recognition by the widespread OB fold

The widespread oligonucleotide/oligosaccharide-binding (OB)-fold recognizes diverse substrates from sugars to nucleic acids and proteins, and plays key roles in genome maintenance, transcription, translation, and tRNA metabolism. OB-containing bacterial Trbp and yeast Arc1p proteins are thought to recognize the tRNA elbow or anticodon regions. Here we report a 2.6 Å co-crystal structure of Aquifex aeolicus Trbp111 bound to tRNA Ile , which reveals that Trbp recognizes tRNAs solely by capturing their 3' ends. Structural, mutational, and biophysical analyses show that the Trbp/EMAPII-like OB fold precisely recognizes the single-stranded structure, 3' terminal location, and specific sequence of the 3' CA dinucleotide — a universal feature of mature tRNAs. Arc1p supplements its OB – tRNA 3' end interaction with additional contacts that involve an adjacent basic region and the tRNA body. This study uncovers a previously unrecognized mode of tRNA recognition by an ancient protein fold, and provides insights into protein-mediated tRNA aminoacylation, folding, localization, trafficking, and piracy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Structure, folding and flexibility of co-transcriptional RNA origami

RNA origami is a method for designing RNA nanostructures that can self-assemble through co-transcriptional folding with applications in nanomedicine and synthetic biology. However, to advance the method further, an improved understanding of RNA structural properties and folding principles is required. Here we use cryogenic electron microscopy to study RNA origami sheets and bundles at sub-nanometre resolution revealing structural parameters of kissing-loop and crossover motifs, which are used to improve designs. In RNA bundle designs, we discover a kinetic folding trap that forms during folding and is only released after 10 h. Furthermore, exploration of the conformational landscape of several RNA designs reveal the flexibility of helices and structural motifs. Finally, sheets and bundles are combined to construct a multidomain satellite shape, which is characterized by individual-particle cryo-electron tomography to reveal the domain flexibility. Together, the study provides a structural basis for future improvements to the design cycle of genetically encoded RNA nanodevices.

77 NANOSCIENCE AND NANOTECHNOLOGY↗
DOE OSTI2021

Comparison of human poly-N-acetyl-lactosamine synthase structure with GT-A fold glycosyltransferases supports a modular assembly of catalytic subsites

Poly-N-acetyl-lactosamine (poly-LacNAc) structures are composed of repeating [-Galβ(1,4)-GlcNAcβ(1,3)-]n glycan extensions. They are found on both N- and O-glycoproteins and glycolipids and play an important role in development, immune function, and human disease. The majority of mammalian poly-LacNAc is synthesized by the alternating iterative action of β1,3-N-acetylglucosaminyltransferase 2 (B3GNT2) and β1,4-galactosyltransferases. B3GNT2 is in the largest mammalian glycosyltransferase family, GT31, but little is known about the structure, substrate recognition, or catalysis by family members. Here we report the structures of human B3GNT2 in complex with UDP:Mg 2+ and in complex with both UDP:Mg 2+ and a glycan acceptor, lacto-N-neotetraose. The B3GNT2 structure conserves the GT-A fold and the DxD motif that coordinates a Mg 2+ ion for binding the UDP-GlcNAc sugar donor. The acceptor complex shows interactions with only the terminal Galβ(1,4)-GlcNAcβ(1,3)- disaccharide unit, which likely explains the specificity for both N- and O-glycan acceptors. Modeling of the UDP-GlcNAc donor supports a direct displacement inverting catalytic mechanism. Comparative structural analysis indicates that nucleotide sugar donors for GT-A fold glycosyltransferases bind in similar positions and conformations without conserving interacting residues, even for enzymes that use the same donor substrate. In contrast, the B3GNT2 acceptor binding site is consistent with prior models suggesting that the evolution of acceptor specificity involves loops inserted into the stable GT-A fold. These observations support the hypothesis that GT-A fold glycosyltransferases employ coevolving donor, acceptor, and catalytic subsite modules as templates to achieve the complex diversity of glycan linkages in biological systems.

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

Early events in G-quadruplex folding captured by time-resolved small-angle X-ray scattering

Abstract Time-resolved small-angle X-ray experiments are reported here that capture and quantify a previously unknown rapid collapse of the unfolded oligonucleotide as an early step in the folding of hybrid 1 and hybrid 2 telomeric G-quadruplex structures. The rapid collapse, initiated by a pH jump, is characterized by an exponential decrease in the radius of gyration from 24.3 to 12.6 Å. The collapse is monophasic and is complete in <600 ms. Additional hand-mixing pH-jump kinetic studies show that slower kinetic steps follow the collapse. The folded and unfolded states at equilibrium were further characterized by SAXS studies and other biophysical tools, showing that G4 unfolding was complete at alkaline pH, but not in LiCl solution as is often claimed. The SAXS Ensemble Optimization Method analysis reveals models of the unfolded state as a dynamic ensemble of flexible oligonucleotide chains with a variety of transient hairpin structures. These results suggest a G4 folding pathway in which a rapid collapse, analogous to molten globule formation seen in proteins, is followed by a confined conformational search within the collapsed particle to form the native contacts ultimately found in the stable folded form.

Biochemistry & Molecular Biology↗
DOE OSTI2022

Cryo-$\mathrm{EM}$ reveals an entangled kinetic trap in the folding of a catalytic $\mathrm{RNA}$

Functional RNAs fold through complex pathways that can contain misfolded “kinetic traps.” A complete model of RNA folding requires understanding the formation of these misfolded states, but they are difficult to characterize because of their transient and potentially conformationally dynamic nature. We used cryo–electron microscopy (cryo-EM) to visualize a long-lived misfolded state in the folding pathway of the Tetrahymena thermophilagroup I intron, a paradigmatic RNA structure-function model system. The structure revealed how this state forms native-like secondary structure and tertiary contacts but contains two incorrectly crossed strands, consistent with a previous model. This incorrect topology mispositions a critical catalytic domain and cannot be resolved locally as extensive refolding is required. This work provides a structural framework for interpreting decades of biochemical and functional studies and demonstrates the power of cryo-EM for the exploration of RNA folding pathways.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

The crystal structure of a Polerovirus exoribonuclease-resistant RNA shows how diverse sequences are integrated into a conserved fold

Exoribonuclease-resistant RNAs (xrRNAs) are discrete elements that block the progression of 5' to 3' exoribonucleases using specifically folded RNA structures. A recently discovered class of xrRNA is widespread in several genera of plant-infecting viruses, within both noncoding and protein-coding subgenomic RNAs. The structure of one such xrRNA from a dianthovirus revealed three-dimensional details of the resistant fold but did not answer all questions regarding the conservation and diversity of this xrRNA class. Here, we present the crystal structure of a representative polerovirus xrRNA that contains sequence elements that diverge from the previously solved structure. This new structure rationalizes previously unexplained sequence conservation patterns and shows interactions not present in the first structure. Together, the structures of these xrRNAs from dianthovirus and polerovirus genera support the idea that these plant virus xrRNAs fold through a defined pathway that includes a programmed intermediate conformation. This work deepens our knowledge of the structure-function relationship of xrRNAs and shows how evolution can craft similar RNA folds from divergent sequences.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

The Promise of Mutation Resistant Drugs for SARS-CoV-2 That Interdict in the Folding of the Spike Protein Receptor Binding Domain

In recent work, we proposed that effective therapeutic drugs aimed at treating the SARS-CoV-2 infection could be developed based on interdicting in the early steps of the folding pathway of key viral proteins, including the receptor binding domain (RBD) of the spike protein. In order to provide for a drug target on the protein, the earliest contact-formation event along the dominant folding pathway of the RBD spike protein was predicted employing the Sequential Collapse Model (SCM). The segments involved in the predicted earliest contact were suggested to provide optimal folding interdiction target regions (FITRs) for potential therapeutic drugs, with a focus on folding interdicting peptides (FIPs). In this paper, we extend our analysis to include 13 known single mutations of the RBD spike protein as well as the triple mutation B1.351 and the recent double mutation B1.617.2. The results show that the location of the FITR does not change in any of the 15 studied mutations, providing for a mutation-resistant drug design strategy for the RBD-spike protein.

Bergasa-Caceres, Fernando↗
DOE OSTI2021

Glucocorticoids activate Yes-associated protein in human vocal fold fibroblasts

Fibrosis of the vocal folds poses a substantive clinical challenge potentially underlying the rapid proliferation of direct steroid injections into the upper airway. The variable clinical response to glucocorticoids (GCs) in the vocal folds is likely related to diversity inherent to GCs and patient-specific, and upstream, cell-specific responses to GCs. Broadly, we hypothesize the disparity in clinical outcomes are due to undesirable effects of GCs on resident fibroblasts. Transcriptome analysis identified significant GC-mediated modulation of Hippo signaling, a known regulator of fibrotic gene expression. Subsequent analysis confirmed GC-mediated YAP activation, a transcriptional co-factor in the Hippo signaling pathway. YAP inhibition attenuated ACTA2 expression in GC-treated human vocal fold fibroblasts. Nuclear localization and phosphorylation at Ser211, however, was not affected by YAP inhibition, suggesting nuclear translocation of YAP is indirectly driven by GR. RNA-seq analysis confirmed the influence of GCs on Wnt signaling, and canonical Wnt signaling target genes were upregulated by GCs. These data implicate YAP and its downstream targets as putative mediators of a pro-fibrotic response to GCs. Therapeutic YAP inhibition may ultimately be clinically relevant and warrants further consideration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

COCOMO2: A Coarse-Grained Model for Interacting Folded and Disordered Proteins

Biomolecular interactions are essential in many biological processes, including complex formation and phase separation processes. Coarse-grained computational models are especially valuable for studying such processes via simulation. Here, we present COCOMO2, an updated residue-based coarse-grained model that extends its applicability from intrinsically disordered peptides to folded proteins. This is accomplished with the introduction of a surface exposure scaling factor, which adjusts interaction strengths based on solvent accessibility, to enable the more realistic modeling of interactions involving folded domains without additional computational costs. COCOMO2 was parametrized directly with solubility and phase separation data to improve its performance on predicting concentration-dependent phase separation for a broader range of biomolecular systems compared to the original version. COCOMO2 enables new applications including the study of condensates that involve IDPs together with folded domains and the study of complex assembly processes. COCOMO2 also provides an expanded foundation for the development of multiscale approaches for modeling biomolecular interactions that span from residue-level to atomistic resolution.

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

Correction to “COCOMO2: A Coarse-Grained Model for Interacting Folded and Disordered Proteins”

Biomolecular interactions are essential in many biological processes, including complex formation and phase separation processes. Coarse-grained computational models are especially valuable for studying such processes via simulation. Here, we present COCOMO2, an updated residue-based coarse-grained model that extends its applicability from intrinsically disordered peptides to folded proteins. This is accomplished with the introduction of a surface exposure scaling factor, which adjusts interaction strengths based on solvent accessibility, to enable the more realistic modeling of interactions involving folded domains without additional computational costs. COCOMO2 was parametrized directly with solubility and phase separation data to improve its performance on predicting concentration-dependent phase separation for a broader range of biomolecular systems compared to the original version. COCOMO2 enables new applications including the study of condensates that involve IDPs together with folded domains and the study of complex assembly processes. COCOMO2 also provides an expanded foundation for the development of multiscale approaches for modeling biomolecular interactions that span from residue-level to atomistic resolution.

Molecular interactions↗
DOE OSTI2022

How Cooperatively Folding Are Homopolymer Molecular Knots?

Detailed thermodynamic analysis of complex systems with multiple stable configurational states allows for insight into the cooperativity of each individual transition. In this work, we derive a heat capacity decomposition comprising contributions from each individual configurational state, which together sum to a baseline heat capacity, and contributions from each state-to-state transition. We apply this analysis framework to a series of replica exchange molecular dynamics simulations of linear and 1-1 coarse-grained homo-oligomer models, which fold into stable, configurationally well-defined molecular knots, in order to better understand the parameters leading to stable and cooperative folding of these knots. We find that a stiff harmonic backbone bending angle potential is key to achieving knots with specific 3D structures. Tuning the backbone equilibrium angle in small increments yields a variety of knot topologies. Populations of different knotted states as a function of temperature can also be manipulated by tuning the backbone torsion stiffness or by adding side-chain beads. We find that sharp total heat capacity peaks for the homo-oligomer knots are largely due to a coil-to-globule transition rather than a cooperative knotting step. Furthermore, in some cases, the cooperativity of globule-to-knot and coil-to-globule transitions is comparable, suggesting that highly cooperative folding to knotted structures can be achieved by refining the model parameters or adding sequence specificity.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Pseudoknot length modulates the folding, conformational dynamics, and robustness of Xrn1 resistance of flaviviral xrRNAs

To understand how RNA dynamics is regulated and connected to its function, we investigate the folding, conformational dynamics and robustness of Xrn1 resistance of a set of flaviviral xrRNAs using SAXS, smFRET and in vitro enzymatic assay. Flaviviral xrRNAs form discrete ring-like 3D structures, in which the length of a conserved longrange pseudoknot (PK2) ranges from 2 bp to 7 bp. We find that xrRNAs’ folding, conformational dynamics and Xrn1 resistance are strongly correlated and highly Mg 2+ - dependent, furthermore, the Mg 2+ -dependence is modulated by PK2 length variations. xrRNAs with long PK2 require less Mg 2+ to stabilize its folding, exhibits reduced conformational dynamics and strong Xrn1 resistance even at low Mg 2+ , and tolerates mutations at key tertiary motifs at high Mg 2+ , which generally are destructive to xrRNAs with short PK2. These results demonstrate an unusual regulatory mechanism of RNA dynamics providing insights into the functions and future biomedical applications of xrRNAs.

59 BASIC BIOLOGICAL SCIENCES↗