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All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Structural basis for p50RhoGAP BCH domain–mediated regulation of Rho inactivation

Significance Small GTPases are binary proteins that rapidly switch between active and inactive states through the actions of GEF- and GTPase-activating proteins (GAPs), respectively. GAPs play significant roles in cellular signaling, and their dysregulation is linked to numerous cancers. Here, we show that the BNIP-2 and Cdc42GAP Homology (BCH) domain of p50RhoGAP, known to autoinhibit the adjacent GAP domain, adopts an intertwined, dimeric structure with unique RhoA interactions. The β5-strand of the BCH domain plays a crucial role in the autoinhibition of the GAP domain. A mutation in the β5-strand destabilizes this autoinhibition and leads to RhoGAP activation. Our studies on the dynamics of the RhoGAP BCH domain will clarify its potential role in cancer and other diseases.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Nanoscale morphological evolution of monocrystalline Pt surfaces during cathodic corrosion

This paper studies the cathodic corrosion of a spherical single crystal of platinum in an aqueous alkaline electrolyte, to map out the detailed facet dependence of the corrosion structures forming during this still largely unexplored electrochemical phenomenon. We find that anisotropic corrosion of the platinum electrode takes place in different stages. Initially, corrosion etch pits are formed, which reflect the local symmetry of the surface: square pits on (100) facets, triangular pits on (111) facets, and rectangular pits on (110) facets. We hypothesize that these etch pits are formed through a ternary metal hydride corrosion intermediate. In contrast to anodic corrosion, the (111) facet corrodes the fastest, and the (110) facet corrodes the slowest. For cathodic corrosion on the (100) facet and on higher-index surfaces close to the (100) plane, the etch pit destabilizes in a second growth stage, by etching faster in the (111) direction, leading to arms in the etch pit, yielding a concave octagon-shaped pit. In a third growth stage, these arms develop side arms, leading to a structure that strongly resembles a self-similar diffusion-limited growth pattern, with strongly preferred growth directions.

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

A coupled human–natural system analysis of freshwater security under climate and population change

Limited water availability, population growth, and climate change have resulted in freshwater crises in many countries. Jordan’s situation is emblematic, compounded by conflict-induced population shocks. Integrating knowledge across hydrology, climatology, agriculture, political science, geography, and economics, we present the Jordan Water Model, a nationwide coupled human–natural-engineered systems model that is used to evaluate Jordan’s freshwater security under climate and socioeconomic changes. The complex systems model simulates the trajectory of Jordan’s water system, representing dynamic interactions between a hierarchy of actors and the natural and engineered water environment. A multiagent modeling approach enables the quantification of impacts at the level of thousands of representative agents across sectors, allowing for the evaluation of both systemwide and distributional outcomes translated into a suite of water-security metrics (vulnerability, equity, shortage duration, and economic well-being). Model results indicate severe, potentially destabilizing, declines in freshwater security. Per capita water availability decreases by approximately 50% by the end of the century. Without intervening measures, >90% of the low-income household population experiences critical insecurity by the end of the century, receiving <40 L per capita per day. Widening disparity in freshwater use, lengthening shortage durations, and declining economic welfare are prevalent across narratives. To gain a foothold on its freshwater future, Jordan must enact a sweeping portfolio of ambitious interventions that include large-scale desalinization and comprehensive water sector reform, with model results revealing exponential improvements in water security through the coordination of supply- and demand-side measures.

42 ENGINEERING↗
DOE OSTI2023

Structure of metallochaperone in complex with the cobalamin-binding domain of its target mutase provides insight into cofactor delivery

G-protein metallochaperone MeaB in bacteria [methylmalonic aciduria type A (MMAA) in humans] is responsible for facilitating the delivery of adenosylcobalamin (AdoCbl) to methylmalonyl-CoA mutase (MCM), the only AdoCbl-dependent enzyme in humans. Genetic defects in the switch III region of MMAA lead to the genetic disorder methylmalonic aciduria in which the body is unable to process certain lipids. Here, we present a crystal structure of Methylobacterium extorquens MeaB bound to a nonhydrolyzable guanosine triphosphate (GTP) analog guanosine-5'-[(β,γ)-methyleno]triphosphate (GMPPCP) with the Cbl-binding domain of its target mutase enzyme (MeMCM cbl ). This structure provides an explanation for the stimulation of the GTP hydrolyase activity of MeaB afforded by target protein binding. We find that upon MCM cbl association, one protomer of the MeaB dimer rotates ~180°, such that the inactive state of MeaB is converted to an active state in which the nucleotide substrate is now surrounded by catalytic residues. Importantly, it is the switch III region that undergoes the largest change, rearranging to make direct contacts with the terminal phosphate of GMPPCP. These structural data additionally provide insights into the molecular basis by which this metallochaperone contributes to AdoCbl delivery without directly binding the cofactor. Our data suggest a model in which GTP-bound MeaB stabilizes a conformation of MCM that is open for AdoCbl insertion, and GTP hydrolysis, as signaled by switch III residues, allows MCM to close and trap its cofactor. Substitutions of switch III residues destabilize the active state of MeaB through loss of protein:nucleotide and protein:protein interactions at the dimer interface, thus uncoupling GTP hydrolysis from AdoCbl delivery.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Genetic switching by the Lac repressor is based on two-state Monod–Wyman–Changeux allostery

High-resolution NMR spectroscopy enabled us to characterize allosteric transitions between various functional states of the dimeric Escherichia coli Lac repressor. In the absence of ligands, the dimer exists in a dynamic equilibrium between DNA-bound and inducer-bound conformations. Binding of either effector shifts this equilibrium toward either bound state. Analysis of the ternary complex between repressor, operator DNA, and inducer shows how adding the inducer results in allosteric changes that disrupt the interdomain contacts between the inducer binding and DNA binding domains and how this in turn leads to destabilization of the hinge helices and release of the Lac repressor from the operator. Based on our data, the allosteric mechanism of the induction process is in full agreement with the well-known Monod–Wyman–Changeux model.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2011

The Structure of a High Fidelity DNA Polymerase Bound to a Mismatched Nucleotide Reveals an ;Ajar; Intermediate Conformation in the Nucleotide Selection Mechanism

To achieve accurate DNA synthesis, DNA polymerases must rapidly sample and discriminate against incorrect nucleotides. Here we report the crystal structure of a high fidelity DNA polymerase I bound to DNA primer-template caught in the act of binding a mismatched (dG:dTTP) nucleoside triphosphate. The polymerase adopts a conformation in between the previously established 'open' and 'closed' states. In this 'ajar' conformation, the template base has moved into the insertion site but misaligns an incorrect nucleotide relative to the primer terminus. The displacement of a conserved active site tyrosine in the insertion site by the template base is accommodated by a distinctive kink in the polymerase O helix, resulting in a partially open ternary complex. We suggest that the ajar conformation allows the template to probe incoming nucleotides for complementarity before closure of the enzyme around the substrate. Based on solution fluorescence, kinetics, and crystallographic analyses of wild-type and mutant polymerases reported here, we present a three-state reaction pathway in which nucleotides either pass through this intermediate conformation to the closed conformation and catalysis or are misaligned within the intermediate, leading to destabilization of the closed conformation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2013

Insights into Diterpene Cyclization from Structure of Bifunctional Abietadiene Synthase from Abies grandis

Abietadiene synthase from Abies grandis (AgAS) is a model system for diterpene synthase activity, catalyzing class I (ionization-initiated) and class II (protonation-initiated) cyclization reactions. Reported here is the crystal structure of AgAS at 2.3 {angstrom} resolution and molecular dynamics simulations of that structure with and without active site ligands. AgAS has three domains ({alpha}, {beta}, and {gamma}). The class I active site is within the C-terminal {alpha} domain, and the class II active site is between the N-terminal {gamma} and {beta} domains. The domain organization resembles that of monofunctional diterpene synthases and is consistent with proposed evolutionary origins of terpene synthases. Molecular dynamics simulations were carried out to determine the effect of substrate binding on enzymatic structure. Although such studies of the class I active site do lead to an enclosed substrate-Mg{sup 2+} complex similar to that observed in crystal structures of related plant enzymes, it does not enforce a single substrate conformation consistent with the known product stereochemistry. Simulations of the class II active site were more informative, with observation of a well ordered external loop migration. This 'loop-in' conformation not only limits solvent access but also greatly increases the number of conformational states accessible to the substrate while destabilizing the nonproductive substrate conformation present in the 'loop-out' conformation. Moreover, these conformational changes at the class II active site drive the substrate toward the proposed transition state. Docked substrate complexes were further assessed with regard to the effects of site-directed mutations on class I and II activities.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Identification of Kaposi Sarcoma Herpesvirus (KSHV) vIRF1 Protein as a Novel Interaction Partner of Human Deubiquitinase USP7

Viral interferon regulatory factor 1 (vIRF1), a Kaposi sarcoma herpesvirus protein, destabilizes p53 by inhibiting p53 acetylation and Hdm2 phosphorylation. This leads to increased ubiquitination and degradation of p53 by Hdm2, which cripples the cellular p53-mediated antiviral response. Ubiquitin-specific protease 7 (USP7) deubiquitinates p53 and Hdm2 and regulates their stability. We identified an EGPS consensus sequence in vIRF1, which is identical to that found in Epstein-Barr virus nuclear antigen 1 (EBNA1) that interacts with the N-terminal domain of USP7 (USP7-NTD). GST pulldown assays demonstrated that vIRF1 interacts with USP7-NTD via its EGPS motif. NMR heteronuclear single quantum correlation (HSQC) analysis revealed chemical perturbations after titration of USP7-NTD with vIRF1 44 SPGEGPSGTG 53 peptide. In contrast, these perturbations were reduced with a mutant vIRF1 peptide, 44 SPGEGPAGTG 53 . Fluorescence polarization analysis indicated that the vIRF1 peptide interacted with USP7-NTD with a K d of 2.0 μm. The crystal structure of the USP7-NTD·vIRF1 peptide complex revealed an identical mode of binding as that of the EBNA1 peptide to USP7-NTD. We also showed that USP7 interacts with vIRF1 in U2OS cells. Decreased levels of p53, but not Hdm2 or ataxia telangiectasia-mutated (ATM), were seen after expression of vIRF1, but not with a vIRF1 mutant protein. Furthermore, our results support a new role for vIRF1 through deregulation of the deubiquitinating enzyme USP7 to inhibit p53-mediated antiviral responses.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Structural and Functional Role of Acetyltransferase hMOF K274 Autoacetylation

Many histone acetyltransferases undergo autoacetylation, either through chemical or enzymatic means, to potentiate enzymatic cognate substrate lysine acetylation, although the mode and molecular role of such autoacetylation is poorly understood. The MYST family of histone acetyltransferases is autoacetylated at an active site lysine residue to facilitate cognate substrate lysine binding and acetylation. Here, we report on a detailed molecular investigation of Lys-274 autoacetylation of the human MYST protein Males Absent on the First (hMOF). A mutational scan of hMOF Lys-274 reveals that all amino acid substitutions of this residue are able to bind cofactor but are significantly destabilized, both in vitro and in cells, and are catalytically inactive for cognate histone H4 peptide lysine acetylation. The x-ray crystal structure of a hMOF K274P mutant suggests that the reduced stability and catalytic activity stems from a disordering of the residue 274-harboring a α2-β7 loop. We also provide structural evidence that a C316S/E350Q mutant, which is defective for cognate substrate lysine acetylation; and biochemical evidence that a K268M mutant, which is defective for Lys-274 chemical acetylation in the context of a K274-peptide, can still undergo quantitative K274 autoacetylation. Together, these studies point to the critical and specific role of hMOF Lys-274 autoacetylation in hMOF stability and cognate substrate acetylation and argues that binding of Ac-CoA to hMOF likely drives Lys-274 autoacetylation for subsequent cognate substrate acetylation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

KPC-2 β-lactamase enables carbapenem antibiotic resistance through fast deacylation of the covalent intermediate

Serine active-site β-lactamases hydrolyze β-lactam antibiotics through the formation of a covalent acyl-enzyme intermediate followed by deacylation via an activated water molecule. Carbapenem antibiotics are poorly hydrolyzed by most β-lactamases owing to slow hydrolysis of the acyl-enzyme intermediate. However, the emergence of the KPC-2 carbapenemase has resulted in widespread resistance to these drugs, suggesting it operates more efficiently. Here, we investigated the unusual features of KPC-2 that enable this resistance. We show that KPC-2 has a 20,000-fold increased deacylation rate compared with the common TEM-1 β-lactamase. Furthermore, kinetic analysis of active site alanine mutants indicates that carbapenem hydrolysis is a concerted effort involving multiple residues. Substitution of Asn170 greatly decreases the deacylation rate, but this residue is conserved in both KPC-2 and non-carbapenemase β-lactamases, suggesting it promotes carbapenem hydrolysis only in the context of KPC-2. X-ray structure determination of the N170A enzyme in complex with hydrolyzed imipenem suggests Asn170 may prevent the inactivation of the deacylating water by the 6α-hydroxyethyl substituent of carbapenems. In addition, the Thr235 residue, which interacts with the C3 carboxylate of carbapenems, also contributes strongly to the deacylation reaction. In contrast, mutation of the Arg220 and Thr237 residues decreases the acylation rate and, paradoxically, improves binding affinity for carbapenems. Thus, the role of these residues may be ground state destabilization of the enzyme-substrate complex or, alternatively, to ensure proper alignment of the substrate with key catalytic residues to facilitate acylation. These findings suggest modifications of the carbapenem scaffold to avoid hydrolysis by KPC-2 β-lactamase.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2016

Thermodynamics, morphology, and kinetics of early-stage self-assembly of π-conjugated oligopeptides

Synthetic oligopeptides containing π-conjugated cores self-assemble novel materials with attractive electronic and photophysical properties. All-atom, explicit solvent molecular dynamics simulations of Asp-Phe-Ala-Gly-OPV3-Gly-Ala-Phe-Asp peptides were used to parameterize an implicit solvent model to simulate early-stage self-assembly. Under low-pH conditions, peptides assemble into β-sheet-like stacks with strongly favorable monomer association free energies of ΔF ≈ -25kBT. Aggregation at high-pH produces disordered aggregates destabilized by Coulombic repulsion between negatively charged Asp termini (ΔF ≈ -5kBT). In simulations of hundreds of monomers over 70 ns we observe the spontaneous formation of up to undecameric aggregates under low-pH conditions. Modeling assembly as a continuous-time Markov process, we infer transition rates between different aggregate sizes and microsecond relaxation times for early-stage assembly. Our data suggests a hierarchical model of assembly in which peptides coalesce into small clusters over tens of nanoseconds followed by structural ripening and diffusion limited aggregation on longer time scales. This work provides new molecular-level understanding of early-stage assembly, and a means to study the impact of peptide sequence and aromatic core chemistry upon the thermodynamics, assembly kinetics, and morphology of the supramolecular aggregates.

36 MATERIALS SCIENCE↗
DOE OSTI2012

Glass formability and the Al-Au system

The aluminum-gold system exhibits various features that suggest high glass formability, such as a deep eutectic, formation of icosahedral clusters in the intermetallic compound near the eutectic minimum and a strongly negative heat of mixing. However, it is very difficult to form a glass with this system. Various issues related to glass formability are discussed using the Al-Au system as a negative test-case. In particular, the atomic level pressure was calculated from first principles for the first time for Al{sub 2}Au, AlAu{sub 2} and AlAu{sub 4} intermetallic compounds. The atomic level pressure is very high in these compounds, suggesting frustrated electronic states which destabilize both crystalline and glassy phases.

36 MATERIALS SCIENCE↗
DOE OSTI2016

Solute drag on perfect and extended dislocations

The drag force exerted on a moving dislocation by a field of mobile solutes is studied in the steady state. The drag force is numerically calculated as a function of the dislocation velocity for both perfect and extended dislocations. The sensitivity of the non-dimensionalized force–velocity curve to the various controlling parameters is assessed, and an approximate analytical force–velocity expression is given. A non-dimensional parameter S characterizing the strength of the solute-dislocation interaction, the background solute fraction , and the dislocation character angle , are found to have the strongest influence on the force–velocity curve. Within the model considered here, a perfect screw dislocation experiences no solute drag, but an extended screw dislocation experiences a non-zero drag force that is about 10 to 30% of the drag on an extended edge dislocation. The solutes can change the spacing between the Shockley partials in both stationary and moving extended dislocations, even when the stacking fault energy remains unaltered. Under certain conditions, the solutes destabilize an extended dislocation by either collapsing it into a perfect dislocation or causing the partials to separate unboundedly. It is proposed that the latter instability may lead to the formation of large faulted areas and deformation twins in low stacking fault energy materials containing solutes, consistent with experimental observations of copper and stainless steel containing hydrogen.

42 ENGINEERING↗
DOE OSTI2012

MOTION IN THE PHOTOGRAVITATIONAL ELLIPTIC RESTRICTED THREE-BODY PROBLEM UNDER AN OBLATE PRIMARY

This paper studies the motion of an infinitesimal mass around seven equilibrium points in the framework of the elliptic restricted three-body problem under the assumption that the primary of the system is a non-luminous, oblate spheroid and the secondary is luminous. A practical application of this case could be the study of the dynamical evolution of dust particles in orbits around a binary system with a dark degenerate primary and a secondary stellar companion. Conditional stability of the motion around the triangular points exists for 0 < {mu} < {mu}{sub c}, where {mu} is the mass ratio. The critical mass ratio value {mu}{sub c} depends on the combined effect of radiation pressure, oblateness, eccentricity, and the semimajor axis of the elliptic orbits; an increase in any of these parameters has destabilizing results on the orbits of the test particles. The overall effect is therefore that the size of the region of stability decreases when the value of these parameters increases. The collinear points and the out-of-plane equilibrium points are found to be unstable for any combination of the parameters considered here. Further, a numerical exploration computing the positions of the triangular points and the critical mass ratio of two binaries RX J0450.1-5856 and Nova Cen 1969 (Cen X-4) is given.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2011

ON THE BLAZHKO EFFECT IN RR LYRAE STARS

The Blazhko effect is a long-term, generally irregular modulation of the light curves that occurs in a sizeable number of RR Lyrae stars. The physical origin of the effect has been a puzzle ever since its discovery over a hundred years ago. We build here upon the recent observational and theoretical work of Szabo et al. on RRab stars who found with hydrodynamical simulations that the fundamental pulsation mode can get destabilized by a 9:2 resonant interaction with the 9th overtone. Alternating pulsation cycles arise, although these remain periodic, i.e., not modulated as in the observations. Here we use the amplitude equation formalism to study this nonlinear, resonant interaction between the two modes. We show that not only does the fundamental pulsation mode break up into a period-two cycle through the nonlinear, resonant interaction with the overtone, but that the amplitudes are modulated, and that in a broad range of parameters the modulations are irregular as in the observations. This irregular behavior is in fact chaotic and arises from a strange attractor in the dynamics.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2011

WHICH PHASE OF THE INTERSTELLAR MEDIUM CORRELATES WITH THE STAR FORMATION RATE?

Nearby spiral galaxies show an extremely tight correlation between tracers of molecular hydrogen (H{sub 2}) in the interstellar medium and tracers of recent star formation, but it is unclear whether this correlation is fundamental or accidental. In the galaxies that have been surveyed to date, H{sub 2} resides predominantly in gravitationally bound clouds cooled by carbon monoxide (CO) molecules, but in galaxies of low metal content the correlations between bound clouds, CO, and H{sub 2} break down, and it is unclear if the star formation rate (SFR) will then correlate with H{sub 2} or with some other quantity. Here, we show that star formation will continue to follow H{sub 2} independent of metallicity. This is not because H{sub 2} is directly important for cooling, but instead because the transition from predominantly atomic hydrogen (H I) to H{sub 2} occurs under the same conditions as a dramatic drop in gas temperature and Bonnor-Ebert mass that destabilizes clouds and initiates collapse. We use this model to compute how SFR will correlate with total gas mass, with mass of gas where the hydrogen is H{sub 2}, and with mass of gas where the carbon is CO in galaxies of varying metallicity, and show that preliminary observations match the trend we predict.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2011

SECULAR CHAOS AND THE PRODUCTION OF HOT JUPITERS

In a planetary system with two or more well-spaced, eccentric, inclined planets, secular interactions may lead to chaos. The innermost planet may gradually become very eccentric and/or inclined as a result of the secular degrees of freedom drifting toward equipartition of angular momentum deficit. Secular chaos is known to be responsible for the eventual destabilization of Mercury in our own solar system. Here we focus on systems with three giant planets. We characterize the secular chaos and demonstrate the criterion for it to occur, but leave a detailed understanding of secular chaos to a companion paper. After an extended period of eccentricity diffusion, the inner planet's pericenter can approach the star to within a few stellar radii. Strong tidal interactions and ensuing tidal dissipation extract orbital energy from the planet and pull it inward, creating a hot Jupiter. In contrast to other proposed channels for the production of hot Jupiters, such a scenario (which we term 'secular migration') explains a range of observations: the pile-up of hot Jupiters at 3 day orbital periods, the fact that hot Jupiters are in general less massive than other radial velocity planets, that they may have misaligned inclinations with respect to stellar spin, and that they have few easily detectable companions (but may have giant companions in distant orbits). Secular migration can also explain close-in planets as low in mass as Neptune; and an aborted secular migration can explain the 'warm Jupiters' at intermediate distances. In addition, the frequency of hot Jupiters formed via secular migration increases with stellar age. We further suggest that secular chaos may be responsible for the observed eccentricities of giant planets at larger distances and that these planets could exhibit significant spin-orbit misalignment.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2011

A NEW STELLAR MIXING PROCESS OPERATING BELOW SHELL CONVECTION ZONES FOLLOWING OFF-CENTER IGNITION

During most stages of stellar evolution the nuclear burning of lighter to heavier elements results in a radial composition profile which is stabilizing against buoyant acceleration, with light material residing above heavier material. However, under some circumstances, such as off-center ignition, the composition profile resulting from nuclear burning can be destabilizing and characterized by an outwardly increasing mean molecular weight. The potential for instabilities under these circumstances and the consequences that they may have on stellar structural evolution remain largely unexplored. In this paper we study the development and evolution of instabilities associated with unstable composition gradients in regions that are initially stable according to linear Schwarzschild and Ledoux criteria. In particular, we study the development of turbulent flow under a variety of stellar evolution conditions with multi-dimensional hydrodynamic simulation; the phases studied include the core helium flash in a 1.25 M{sub Sun} star, the core carbon flash in a 9.3 M{sub Sun} star, and oxygen shell burning in a 23 M{sub Sun} star. The results of our simulations reveal a mixing process associated with regions having outwardly increasing mean molecular weight that reside below convection zones. The mixing is not due to overshooting from the convection zone, nor is it due directly to thermohaline mixing which operates on a timescale several orders of magnitude larger than the simulated flows. Instead, the mixing appears to be due to the presence of a wave field induced in the stable layers residing beneath the convection zone which enhances the mixing rate by many orders of magnitude and allows a thermohaline type mixing process to operate on a dynamical, rather than thermal, timescale. The mixing manifests itself in the form of overdense and cold blob-like structures originating from density fluctuations at the lower boundary of convective shell and 'shooting' down into the core. They are enriched with nuclearly processed material, hence leaving behind traces of higher mean molecular weight. In these regions, we find that initially smooth composition gradients steepen into stair-step-like profiles in which homogeneous, mixed regions are separated by composition jumps. These step-like profiles are then seen to evolve by a process of interface migration driven by turbulent entrainment. We discuss our results in terms of related laboratory phenomena and associated theoretical developments. We also discuss the degree to which the simulated mixing rates depend on the numerical resolution, and what future steps can be taken to capture the mixing rates accurately.

79 ASTRONOMY AND ASTROPHYSICS↗