Relevant States Research Articles

Elevator transport mechanism in SLC4 transporters: Insights from new inward facing cryo-EM structures of AE1.

The SLC4 transporters are responsible for the transport of various ions, such as HCO3−, CO32−, Cl−, Na+, and NH3+H+, necessary for maintenance of pH, blood pressure and ion homeostasis in the body. Among them, the AE1 transporter protein (Anion Exchanger 1, Band 3, SLC4A1), a Na+-independent Cl−/HCO3− exchanger, has been extensively studied both from theoretical and experimental perspective, due to its peculiarly high rate of transport. An outward facing (OF) open structure of the human AE1 has been previously resolved and substrate binding sites in it have been identified both from computational, functional mutagenesis, and cryoEM studies. However, detailed understanding of the transport mechanism of AE1 and other members of the SLC4 family is hindered by lack of structures of other catalytically relevant states. In the present work we report cryoEM structures of dimers of bovine AE1 (bAE1), which feature inward facing (IF) open monomers. Moreover, mixed dimers where one monomer is in IF and the other - in OF state, were also resolved, indicating independent movement of monomers in the dimers. The new IF and OF states of bAE1 provide unambiguous structural evidence for elevator transport mechanism with a small vertical shift of the core domain with respect to the rigid gate domain. An unexpected elongation of transmembrane helix (TM) 11 and the accompanying reorganization of intracellular loop (IL) 5 from beta-hairpin into alpha-helical geometry is also observed in the IF state. Computational modelling demonstrates different anion dynamics at both sides of the lipid membrane. The small structural reorganization during the OF to IF transition, and the fast anion permeation into the IF and OF cavities of AE1 emerge as possible explanations of the observed high transport rate of this protein.

Spectral splitting of the lasing emission of nitrogen ions pumped by 800-nm femtosecond laser pulses.

We report on a spectral splitting effect of the cavity-less lasing emission of nitrogen ions at 391.4 nm pumped by 800-nm femtosecond laser pulses. It was found that with the increase of the nitrogen gas pressure and pump pulse energy, both R and P branches experience spectral splitting. With an external injected seeding pulse, a similar split spectral line is observed for the amplified emission. In contrast, for the fluorescence radiation, no such spectral splitting phenomenon is observed with much more abundant R branch structures. Our theoretical model considers gas ionization by the pump pulse, the competition of excitation of all relevant electronic and vibrational states, and an amplification of the seeding pulse in the plasma with a population inversion. Our simulation reproduces this spectral splitting effect, which is attributed to the gain saturation resulting in the oscillation of the amplitude of the amplified signal.

Fermionic-propagator and alternating-basis quantum Monte Carlo methods for correlated electrons on a lattice.

Ultracold-atom simulations of the Hubbard model provide insights into the character of charge and spin correlations in and out of equilibrium. The corresponding numerical simulations, on the other hand, remain a significant challenge. We build on recent progress in the quantum Monte Carlo (QMC) simulation of electrons in continuous space and apply similar ideas to the square-lattice Hubbard model. We devise and benchmark two discrete-time QMC methods, namely the fermionic-propagator QMC (FPQMC) and the alternating-basis QMC (ABQMC). In FPQMC, the time evolution is represented by snapshots in real space, whereas the snapshots in ABQMC alternate between real and reciprocal space. The methods may be applied to study equilibrium properties within the grand-canonical or canonical ensemble, external field quenches, and even the evolution of pure states. Various real-space/reciprocal-space correlation functions are also within their reach. Both methods deal with matrices of size equal to the number of particles (thus independent of the number of orbitals or time slices), which allows for cheap updates. We benchmark the methods in relevant setups. In equilibrium, the FPQMC method is found to have an excellent average signand, in some cases, yields correct results even with poor imaginary-time discretization. ABQMC has a significantly worse average sign, but also produces good results. Out of equilibrium, FPQMC suffers from a strong dynamical signproblem. On the contrary, in ABQMC, the signproblem is not time-dependent. Using ABQMC, we compute survival probabilities for several experimentally relevant pure states.

An Open-Cuboidal [Fe3S4] Cluster Characterized in Both Biologically Relevant Redox States

Synthetic analogues of the three common types of Fe-S clusters found in biology─diamond-core [Fe2S2] clusters, open-cuboidal [Fe3S4] clusters, and cuboidal [Fe4S4] clusters─have been reported in each biologically relevant redox state with one exception: the open-cuboidal [Fe3S4]+ cluster. Here, we describe the synthesis and characterization of an open-cuboidal [Fe3S4] cluster in both biologically relevant redox states: [Fe3S4]+ and [Fe3S4]0. Like their biological counterparts, the oxidized cluster has a spin-canted, S = 1/2 ground state, and the reduced cluster has an S = 2 ground state. Structural analysis reveals that the [Fe3S4] core undergoes substantial contraction upon oxidation, in contrast to the minimal structural changes observed for the only [Fe3S4] protein for which high-resolution structures are available in both redox states (Azotobacter vinelandii ferredoxin I; Av FdI). This difference between the synthetic models and Av FdI is discussed in the context of electron transfer by [Fe3S4] proteins.

Novel Lennard-Jones Parameters for Cysteine and Selenocysteine in the AMBER Force Field.

Cysteine is a common amino acid with a thiol group that plays a pivotal role in a variety of scenarios in redox biochemistry. In contrast, selenocysteine, the 21st amino acid, is only present in 25 human proteins. Classical force-field parameters for cysteine and selenocysteine are still scarce. In this context, we present a methodology to obtain Lennard-Jones parameters for cysteine and selenocysteine in different physiologically relevant oxidation and protonation states. The new force field parameters obtained in this work are available at https://github.com/MALBECC/AMBER-parameters-database. The parameters were adjusted to reproduce water radial distribution functions obtained by density functional theory ab initio molecular dynamics. We validated the results by evaluating the impact of the choice of parameters on the structure and dynamics in classical molecular dynamics simulations of representative proteins containing catalytic cysteine/selenocysteine residues. There are significant changes in protein structure and dynamics depending on the parameters choice, specifically affecting the residues close to the catalytic sites.

Understanding the Stringent Response: Experimental Context Matters.

As rapidly growing bacteria begin to exhaust essential nutrients, they enter a state of reduced growth, ultimately leading to stasis or quiescence. Investigation of the response to nutrient limitation has focused largely on the consequences of amino acid starvation, known as the "stringent response." Here, an uncharged tRNA in the A-site of the ribosome stimulates the ribosome-associated protein RelA to synthesize the hyperphosphorylated guanosine nucleotides (p)ppGpp that mediate a global slowdown of growth and biosynthesis. Investigations of the stringent response typically employ experimental methodologies that rapidly stimulate (p)ppGpp synthesis by abruptly increasing the fraction of uncharged tRNAs, either by explicit amino starvation or by inhibition of tRNA charging. Consequently, these methodologies inhibit protein translation, thereby interfering with the cellular pathways that respond to nutrient limitation. Thus, complete and/or rapid starvation is a problematic experimental paradigm for investigating bacterial responses to physiologically relevant nutrient-limited states.

Developing improved measures of non-Gaussianity and Gaussianity for quantum states based on normalized Hilbert–Schmidt distance

Non-Gaussianity of quantum states is a very important source for quantum information technology and can be quantified by using the known squared Hilbert–Schmidt distance recently introduced by Genoni et al. (Phys. Rev. A 78 042327 (2007)). It is, however, shown that such a measure has many imperfects such as the lack of the swapping symmetry and the ineffectiveness evaluation of even Schrödinger-cat-like states with small amplitudes. To deal with these difficulties, we propose an improved measure of non-Gaussianity for quantum states and discuss its properties in detail. We then exploit this improved measure to evaluate the non-Gaussianities of some relevant single-mode non-Gaussian states and multi-mode non-Gaussian entangled states. These results show that our measure is reliable. We also introduce a modified measure for Gaussianity following Mandilara and Cerf (Phys. Rev. A 86 030102(R) (2012)) and establish a conservation relation of non-Gaussianity and Gaussianity of a quantum state.

Investigating the conformational landscape of AlphaFold2-predicted protein kinase structures.

Protein kinases are a family of signaling proteins, crucial for maintaining cellular homeostasis. When dysregulated, kinases drive the pathogenesis of several diseases, and are thus one of the largest target categories for drug discovery. Kinase activity is tightly controlled by switching through several active and inactive conformations in their catalytic domain. Kinase inhibitors have been designed to engage kinases in specific conformational states, where each conformation presents a unique physico-chemical environment for therapeutic intervention. Thus, modeling kinases across conformations can enable the design of novel and optimally selective kinase drugs. Due to the recent success of AlphaFold2 in accurately predicting the 3D structure of proteins based on sequence, we investigated the conformational landscape of protein kinases as modeled by AlphaFold2. We observed that AlphaFold2 is able to model several kinase conformations across the kinome, however, certain conformations are only observed in specific kinase families. Furthermore, we show that the per residue predicted local distance difference test can capture information describing structural flexibility of kinases. Finally, we evaluated the docking performance of AlphaFold2 kinase structures for enriching known ligands. Taken together, we see an opportunity to leverage AlphaFold2 models for structure-based drug discovery against kinases across several pharmacologically relevant conformational states. All code used in the analysis is freely available at https://github.com/Harmonic-Discovery/AF2-kinase-conformational-landscape.

Thouless pumping and topology

Thouless pumping provides one of the simplest manifestations of topology in quantum systems, and has attracted a lot of recent interest, both theoretically and experimentally. Since the seminal works by Thouless and Niu in 1983 and 1984, it is argued that the quantization of the pumped charge is robust against weak disorder, but a clear characterization of the localization properties of the relevant states, and the breakdown of quantized transport in the presence of interaction or out of the adiabatic approximation, has been long debated. Thouless pumping is also the first example of a topological phase emerging in a periodically-driven system. Driven systems can exhibit exotic topological phases without any static analogue and have been the subject of many recent proposals both in fermionic and bosonic systems in diverse platforms ranging from cold atoms to photonics and condensed matter systems. In this respect, this review has a twofold purpose: On the one hand, it serves as a basis to understand the robustness of the topology of slowly-driven systems per se; On the other hand, it highlights the rich properties of topological pumps and their diverse range of applications, for instance, in systems with synthetic dimensions or for understanding higher-order topological phases. These examples underline the relevance of topological pumping for the fast growing field of topological quantum matter.

Illegal, Unreported, and Unregulated Fishing Governance in Disputed Maritime Areas: Reflections on the International Legal Obligations of States

Illegal, unreported, and unregulated (IUU) fishing in the disputed maritime areas causes significant damage to the marine ecology and authorized fisheries, increases the risk of conflicts among disputed states, and violates human rights at sea. Both unilateral measures and cooperative governance for IUU fishing are often inadequate in these areas. In light, this study aims to clarify the regulatory obligations of relevant states and explore feasible solutions based on international cooperation to promote IUU governance in disputed areas worldwide. The rapidly evolving international fisheries legal framework requires that states, such as coastal states, flag states, port states, or market states, fulfill their respective obligations to prevent and deter IUU and that the presence of disputes in a specific maritime area does not typically constitute grounds for derogation from these obligations or exemption from possible state responsibility. However, the implications of the conflicting claims in disputed maritime areas should be taken into consideration while interpreting and applying international legal rules. Therefore, this study suggests that regional and inter-regional cooperation is necessary for states to fulfill their obligations to regulate IUU fishing and prevent state responsibilities under international law. Parties to the dispute, as well as third parties, are encouraged to participate in the cooperative mechanism in order to coordinate legislative and enforcement measures and advance the institutionalization of IUU fishing regulation in the disputed maritime areas, which will not only advances the effective governance of IUU fishing but also reduces tensions among the disputing states and contributes to the peaceful settlement of the dispute.

Combining small angle X-ray scattering (SAXS) with protein structure predictions to characterize conformations in solution.

Accurate protein structure predictions, enabled by recent advances in machine learning algorithms, provide an entry point to probing structural mechanisms and to integrating and querying many types of biochemical and biophysical results. Limitations in such protein structure predictions can be reduced and addressed through comparison to experimental Small Angle X-ray Scattering (SAXS) data that provides protein structural information in solution. SAXS data can not only validate computational predictions, but can improve conformational and assembly prediction to produce atomic models that are consistent with solution data and biologically relevant states. Here, we describe how to obtain protein structure predictions, compare them to experimental SAXS data and improve models to reflect experimental information from SAXS data. Furthermore, we consider the potential for such experimentally-validated protein structure predictions to broadly improve functional annotation in proteins identified in metagenomics and to identify functional clustering on conserved sites despite low sequence homology.

Effects of Solvent Dielectric on Thermally Activated Delayed Fluorescence: A Predictive Computational Polarization Consistent Approach

We study computationally thermally activated delayed fluorescence (TADF) in donor-acceptor compounds. The relevant electronic excited states that are strongly affected by the dielectric environment are treated by a polarization consistent framework. The high fidelity potential energy surfaces are used following a quantum-mechanical Fermi's golden rule (FGR) picture to calculate rates of intersystem crossing (ISC) and reverse intersystem crossing (RISC). To demonstrate the potency of the approach, we consider isomers of benzonitrile functionalized tert-butyl-substituted dimethylacridine (DMAC-BN), which were recently found to perform well as TADF emitters. The calculated excited state energies that appear to reproduce well measured spectral trends with respect to the dielectric constant are used to parametrize ISC/RISC FGR rates. The calculated rates reproduce well measured rates, whereas semiclassical based rates are grossly underestimated. In particular, we find in agreement with the recent experimental study [Phys. Rev. Appl.2019, 12, 044021] that the ortho and meta isomers are significantly more effective as TADF emitters. The computational framework provides valuable insight at the molecular level into RISC rates and therefore can contribute to the design of materials of increased TADF efficiency.

Low‐lying states of FeSin−/0/+ (n = 1‐2) clusters from DMRG‐CASPT2 calculations

AbstractThe electronic states of FeSin−/0/+ (n = 1‐2) clusters have been investigated with DFT, CASPT2, and DMRG‐CASPT2 methods. By using relatively large active spaces, the DMRG‐CASPT2 method is found to provide highly accurate relative energies for the various relevant electronic states. Leading configurations, bond distances, harmonic vibrational frequencies, and relative energies for the low‐lying states of the title clusters are reported. Electron detachment energies for the ground states of the anionic and neutral clusters were estimated at the DMRG‐CASPT2 level. Franck‐Condon factor simulations were performed for transitions from the anionic ground state to the neutral ground state and from the neutral ground state to the cationic ground state with the purpose to produce the vibrational progressions.

Mutual neutralization in H++H− collisions: An improved theoretical model

The total and differential cross sections of mutual neutralization in ${\mathrm{H}}^{+}+{\mathrm{H}}^{\ensuremath{-}}$ collisions are calculated ab initio and fully quantum mechanically for energies between 0.001 and 600 eV. Effects which have not previously been considered in studies on mutual neutralization (MN) for this system, such as inclusion of rotational couplings and autoionization, are investigated. Adiabatic potential curves corresponding to the relevant states of $^{1}\mathrm{\ensuremath{\Sigma}}_{g}^{+}$, $^{1}\mathrm{\ensuremath{\Sigma}}_{u}^{+}$, $^{1}\mathrm{\ensuremath{\Pi}}_{g}$ and $^{1}\mathrm{\ensuremath{\Pi}}_{u}$ symmetries as well as radial and rotational nonadiabatic couplings are computed ab initio. A quasidiabatic model is developed and applied in order to investigate the importance of higher excited states as well as the inclusion of autoionization. Molecular data for the lowest electronic resonant state in each symmetry are obtained by performing electron scattering calculations. It is shown that rotational couplings cause a significant increase of the total MN cross section while autoionization plays a minor role as a loss mechanism. Additionally, a differential cross section is obtained that is symmetric around $\ensuremath{\theta}={90}^{\ensuremath{\circ}}$. This result is in disagreement with a previous theoretical calculation where it was found that the differential cross section is dominated by backwards scattering.

An equidistance/equiratio method of maritime delimitation on the Earth ellipsoid

The United Nations Convention on the Law of the Sea provides only basic legal principles for maritime delimitation disputes among coastal states. The implementation of maritime delimitation requires the comprehensive use of legal, political, and technical means by relevant states to generate the expected equitable results. Accurate calculation of the maritime delimitation boundary provides the basis for this equitable delimitation. Although the final determination of the maritime boundary is the result of diplomatic agreement, both disputing parties need a reasonable starting line as the point of departure for negotiations. As such, the equidistance/equiratio line can aid in this important task. The traditional three-point methods have many disadvantages, however, including a complex calculation process, dependence on map projections, and difficulty in calculating the equiratio line. Although the elastic method, water-line method, and mesh-points method can be used to calculate the equidistance/equiratio line, the boundary pattern is complex and the number of turning points is large. As a result, a great deal of adjustment and simplification is required, and simplifying the boundary line requires a complex diplomatic negotiation process. To solve these problems, we proposed a new three-point equidistance/equiratio method based on the Earth ellipsoid, which is called pendulum method. By choosing different geographical scenarios, we used the new method and CARIS to calculate the boundary and compared the demarcation results. The results demonstrated that the proposed method could generate an equidistance/equiratio line in various scenes using a unified algorithm. The algorithm was simple and efficient and was not limited by the map projection.

A knowledge integration strategy for the selection of a robust multi-stress biomarkers panel for Bacillus subtilis

One challenge in the engineering of biological systems is to be able to recognise the cellular stress states of bacterial hosts, as these stress states can lead to suboptimal growth and lower yields of target products. To enable the design of genetic circuits for reporting or mitigating the stress states, it is important to identify a relatively reduced set of gene biomarkers that can reliably indicate relevant cellular growth states in bacteria. Recent advances in high-throughput omics technologies have enhanced the identification of molecular biomarkers specific states in bacteria, motivating computational methods that can identify robust biomarkers for experimental characterisation and verification. Focused on identifying gene expression biomarkers to sense various stress states in Bacillus subtilis, this study aimed to design a knowledge integration strategy for the selection of a robust biomarker panel that generalises on external datasets and experiments. We developed a recommendation system that ranks the candidate biomarker panels based on complementary information from machine learning model, gene regulatory network and co-expression network. We identified a recommended biomarker panel showing high stress sensing power for a variety of conditions both in the dataset used for biomarker identification (mean f1-score achieved at 0.99), as well as in a range of independent datasets (mean f1-score achieved at 0.98). We discovered a significant correlation between stress sensing power and evaluation metrics such as the number of associated regulators in a B. subtilis gene regulatory network (GRN) and the number of associated modules in a B. subtilis co-expression network (CEN). GRNs and CENs provide information relevant to the diversity of biological processes encoded by biomarker genes. We demonstrate that quantitatively relating meaningful evaluation metrics with stress sensing power has the potential for recognising biomarkers that show better sensitivity and robustness to an extended set of stress conditions and enable a more reliable biomarker panel selection.

Breathing and Tilting: Mesoscale Simulations Illuminate Influenza Glycoprotein Vulnerabilities.

Influenza virus has resurfaced recently from inactivity during the early stages of the COVID-19 pandemic, raising serious concerns about the nature and magnitude of future epidemics. The main antigenic targets of influenza virus are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Whereas the structural and dynamical properties of both glycoproteins have been studied previously, the understanding of their plasticity in the whole-virion context is fragmented. Here, we investigate the dynamics of influenza glycoproteins in a crowded protein environment through mesoscale all-atom molecular dynamics simulations of two evolutionary-linked glycosylated influenza A whole-virion models. Our simulations reveal and kinetically characterize three main molecular motions of influenza glycoproteins: NA head tilting, HA ectodomain tilting, and HA head breathing. The flexibility of HA and NA highlights antigenically relevant conformational states, as well as facilitates the characterization of a novel monoclonal antibody, derived from convalescent human donor, that binds to the underside of the NA head. Our work provides previously unappreciated views on the dynamics of HA and NA, advancing the understanding of their interplay and suggesting possible strategies for the design of future vaccines and antivirals against influenza.

A pragmatic protocol for determining charge transfer states of molecules at metal surfaces by constrained density functional theory.

Electron transfer from a metal surface to a molecule is very important at the gas-surface interface, which can lead to electron-mediated energy transfer during molecular scattering from the surface, as evidenced by numerous state-to-state molecular beam experiments of NO and CO scattering from noble metal surfaces. However, it remains challenging to determine relevant charge-transfer states and their nonadiabatic couplings from first principles in such systems involving a continuum of metallic electronic states. In this work, we propose a pragmatic protocol for this purpose based on the constrained density functional theory (CDFT) approach. In particular, we discuss the influence of the charge partitioning algorithm used in CDFT to define the constraint property in molecule-metal systems. It is found that the widely used Bader charge analysis is adequate to define the physically sound CDFT diabatic states corresponding to a molecule with or without extra electron transferred from the metal. Numerical tests validate that the proposed CDFT scheme properly describes the electron transfer behaviors in several benchmark systems, namely, NO or CO interacting with Au(111) or Ag(111). The effects of the surface work function and the molecular electron affinity on electron transfer are discussed in detail by comparing the CDFT states of the four systems. This pragmatic CDFT protocol lays the foundation for constructing accurate global diabatic potential energy surfaces for these important systems and can be generalized to study other interfacial electron transfer related problems.

Ambient-temperature liquid jet targets for high-repetition-rate HED discovery science

High-power lasers can generate energetic particle beams and astrophysically relevant pressure and temperature states in the high-energy-density (HED) regime. Recently-commissioned high-repetition-rate (HRR) laser drivers are capable of producing these conditions at rates exceeding 1 Hz. However, experimental output from these systems is often limited by the difficulty of designing targets that match these repetition rates. To overcome this challenge, we have developed tungsten microfluidic nozzles, which produce a continuously replenishing jet that operates at flow speeds of approximately 10 m/s and can sustain shot frequencies up to 1 kHz. The ambient-temperature planar liquid jets produced by these nozzles can have thicknesses ranging from hundreds of nanometers to tens of micrometers. In this work, we illustrate the operational principle of the microfluidic nozzle and describe its implementation in a vacuum environment. We provide evidence of successful laser-driven ion acceleration using this target and discuss the prospect of optimizing the ion acceleration performance through an in situ jet thickness scan. Future applications for the jet throughout HED science include shock compression and studies of strongly heated nonequilibrium plasmas. When fielded in concert with HRR-compatible laser, diagnostic, and active feedback technology, this target will facilitate advanced automated studies in HRR HED science, including machine learning-based optimization and high-dimensional statistical analysis.

A robust nonlinear backstepping control scheme for hybrid AC/DC microgrids to improve dynamic stability against external disturbances

In this work, robust nonlinear controllers are designed for converters interfacing power generation and energy storage including DC- and AC-sides in hybrid AC/DC microgrid for improving the dynamic stability against external disturbances. The robust switching control inputs for all these interfacing converters and excitation as well as steam-valving control laws for the synchronous generators are determined using a nonlinear backstepping approach. The dynamic elements of the hybrid AC/DC microgrid are modeled by considering the effects of external disturbances where these disturbances reflect the effects of modeling errors, measurement noises, and parametric uncertainties. The robust control inputs for different elements in the microgrid are determined by guaranteeing the convergences of all relevant states, associated with different elements, toward their desired values while properly bounding the effects of disturbances. Control Lyapunov functions (CLFs) are formulated, during the proposed controller design process, to assess the dynamic stability. Simulation studies are conducted on a hybrid AC/DC microgrid to validate the effectiveness by observing the overall power balance with changes in the system while comparing with an existing sliding mode controller (ESMC). Simulation results clearly indicate robustness of the newly proposed controller through the improvement in the overall dynamic performance of the hybrid AC/DC microgrid over the ESMC.