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DOE OSTI2012

Structural Insight into the Ion-Exchange Mechanism of the Sodium/Calcium Exchanger

Sodium/calcium (Na{sup +}/Ca{sup 2+}) exchangers (NCX) are membrane transporters that play an essential role in maintaining the homeostasis of cytosolic Ca{sup 2+} for cell signaling. We demonstrated the Na{sup +}/Ca{sup 2+}-exchange function of an NCX from Methanococcus jannaschii (NCX{_}Mj) and report its 1.9 angstrom crystal structure in an outward-facing conformation. Containing 10 transmembrane helices, the two halves of NCX{_}Mj share a similar structure with opposite orientation. Four ion-binding sites cluster at the center of the protein: one specific for Ca{sup 2+} and three that likely bind Na{sup +}. Two passageways allow for Na{sup +} and Ca{sup 2+} access to the central ion-binding sites from the extracellular side. Based on the symmetry of NCX{_}Mj and its ability to catalyze bidirectional ion-exchange reactions, we propose a structure model for the inward-facing NCX{_}Mj.

36 MATERIALS SCIENCE↗

DOE OSTI2018

Structural basis for the interaction between DJ-1 and Bcl-XL

Highlights: • Oxidized, but not reduced, DJ-1 interacts with Bcl-X{sub L}. • C-terminal α8-helix of DJ-1 acts as a binding motif for Bcl-X{sub L}. • C-terminal α8-helix of DJ-1 binds to the BH3 peptide-binding groove in Bcl-X{sub L}. • A conserved binding mode of the Bcl-X{sub L}/DJ-1 and other Bcl-X{sub L}/BH3 peptide complexes. • Understanding of structural basis for the binding between DJ-1 and Bcl-X{sub L}. DJ-1 is a multifunctional protein associated with Parkinson's disease (PD) and tumorigenesis. In response to ultraviolet B (UVB) irradiation, DJ-1 is translocated into the mitochondria, and its interaction with the mitochondrial protein Bcl-X{sub L} protects cells against death. In this study, we characterized the molecular interaction between DJ-1 and Bcl-X{sub L} by NMR spectroscopy. The NMR chemical shift perturbation data demonstrated that the oxidized but not the reduced form of DJ-1 binds to the predominantly hydrophobic groove surrounded by the BH1–BH3 domains in Bcl-X{sub L}. In addition, our results showed that the C-terminal α8-helix peptide (Cpep) of DJ-1 binds to the pro-apoptotic BH3 peptide-binding hydrophobic groove in Bcl-X{sub L} and, thus, acts as a Bcl-X{sub L}-binding motif. In combination with the NMR chemical shift perturbation data, a refined structural model of the Bcl-X{sub L}/DJ-1 Cpep complex revealed that the binding mode is remarkably similar to that of other Bcl-X{sub L}/pro-apoptotic BH3 peptide complexes. Taken together, our results provide a structural basis for the binding mechanism between DJ-1 and Bcl-X{sub L}, which will contribute to molecular understanding of the role of mitochondrial DJ-1 in Bcl-X{sub L} regulation in response to oxidative stress.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

TEM study of the (SbS){sub 1+δ}(NbS{sub 2}){sub n}, (n=1, 2, 3; δ~1.14, 1.20) misfit layer phases

In the Sb–Nb–S system four new misfit layer phases have been found and carefully investigated via Transmission Electron Microscopy (TEM). Their structures are of composite modulated structure type with stoichiometries that can be formulated as (SbS){sub 1+δ}(NbS{sub 2}){sub n}; for n=1, δ~1.14 and 1.19; for n=2, δ~1.18 and for n=3, δ~1.19. Selected Area Electron Diffraction (SAED) patterns show an almost commensurate fit between the pseudo-tetragonal (SbS) and the pseudo-orthohexagonal (NbS{sub 2}){sub n} subcells along the misfit direction a, with 3(SbS)≈5(NbS{sub 2}), being b the same for both sub-lattices and c the stacking direction. For n=1, a commensurate phase with 4a{sub SbS}=7a{sub NbS2} has also been observed. In addition to the characteristic misfit and associated modulation of the two sub-structures, a second modulation is also present which appears to be primarily associated with the (SbS) sub-structure of both the n=1 and n=2 phases. High Resolution Transmission Electron Microscopy (HRTEM) images show ordered stacking sequences between the (SbS) and (NbS{sub 2}){sub n} lamellae for each of the four phases, however, disordered intergrowths were also occasionally found. Most of the crystals showed different kinds of twinning defects on quite a fine scale. Many crystals showed curled up edges. In some cases the lamellar crystals were entirely folded giving rise to similar diffraction patterns as found for cylindrical crystals. - Graphical abstract: Idealized structure models of the first three members of the homologous series (SbS){sub 1+δ}(NbS{sub 2}){sub n}. - Highlights: • Transmission Electron Microscopy study of misfit layer sulfides (SbS){sub 1+δ}(NbS{sub 2}){sub n}. • The structures consist of a (SbS) layer interleaved between n (NbS{sub 2}) layers. • Two different members n=1, one n=2 and one n=3 have been studied. • Twinning, intergrowths and different modulations in the (SbS) substructure.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2016

Complexation and phase evolution at dimethylformamide-Ag(111) interfaces

The interaction of solvent molecules with metallic surfaces impacts many interfacial chemical processes. We investigate the chemical and structure evolution that follows adsorption of the polar solvent dimethylformamide (DMF) on Ag(111). An Ag(DMF) 2 coordination complex forms spontaneously by DMF etching of Ag(111), yielding mixed films of the complexes and DMF. Utilizing ultrahigh vacuum scanning tunneling microscopy (UHV-STM), in combination with X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) computations, we map monolayer phases from the 2-D gas regime, consisting of a binary mixture of DMF and Ag(DMF) 2 , through the saturation monolayer limit, in which these two chemical species phase separate into ordered islands. Structural models for the near-square DMF phase and the chain-like Ag(DMF) 2 phase are presented and supported by DFT computation. Interface evolution is summarized in a surface pressure-composition phase diagram, which allows structure prediction over arbitrary experimental conditions. In conclusion, this work reveals new surface coordination chemistry for an important electrolyte-electrode system, and illustrates how surface pressure can be used to tune monolayer phases.

2-D phases↗

DOE OSTI2014

AN ATMOSPHERIC STRUCTURE EQUATION FOR GRAIN GROWTH

We present a method to include the evolution of the grain size and grain opacity κ{sub gr} in the equations describing the structure of protoplanetary atmospheres. The key assumption of this method is that a single grain size dominates the grain size distribution at any height r. In addition to following grain growth, the method accounts for mass deposition by planetesimals and grain porosity. We illustrate this method by computation of a simplified atmosphere structure model. In agreement with previous works, grain coagulation is seen to be very efficient. The opacity drops to values much below the often-used ''interstellar medium opacities'' (∼1 cm{sup 2} g{sup –1}) and the atmosphere structure profiles for temperature and density resemble that of the grain-free case. Deposition of planetesimals in the radiative part of the atmosphere hardly influences this outcome as the added surface is quickly coagulated away. We observe a modest dependence on the internal structure (porosity), but show that filling factors cannot become too large because of compression by gas drag.

79 ASTRONOMY AND ASTROPHYSICS↗

DOE OSTI2024

Evaluation of Composite Structural Materials for Heliostat Cost Reduction

Structures manufactured from steel comprise up to 40% of a CSP heliostat's cost. Composite structures represent a potential opportunity to reduce this cost. A reference heliostat structural model has been created with a reflector area of 25m 2 . The design, constructed of low-carbon steel, pro-vides baseline deflection and stiffness under a 21 m/s operating wind speeds. Wind loads on the tracker structure are determined for both operating and stow conditions. An established roster of suitable metal alternative materials is considered including: glass, basalt, and carbon reinforced polymer (GFRP, BFRP, and CFRP respectively). Three heliostat components are investigated: the pylon, torque tube, and the purlin-strut assembly. Composite material properties are substituted for those of steel, and the beams are re-sized to match the original steel components' deflection under given wind loads. Weight and cost changes resulting from this resizing are evaluated. It is found that GFRP and BFRP represent a 3X–6X cost premium for the same operating deflection character-istics as steel across all three investigated component classes; with weight reduction only achieved for the purlin-strut assembly. While CFRP components can achieve approximately 25–75% weight savings depending on the application, this comes with a 9X–14X cost increase over the steel base-line for tube-type structures and roughly 5X cost increase when replacing c-channel structures. This work does not rule out the possibility of cost savings when the heliostat design and kinematics to take advantage of composites' specific properties.

14 SOLAR ENERGY↗

DOE OSTI2022

MoO x S y /Ni 3 S 2 Microspheres on Ni Foam as Highly Efficient, Durable Electrocatalysts for Hydrogen Evolution Reaction

Hydrogen energy derived from water splitting is the cleanest renewable energy source, but it is also very challenging to achieve because the hydrogen evolution reaction (HER) requires highly efficient and low-cost electrocatalysts. Here, we have fabricated a novel hierarchical system of amorphous molybdenum oxy/sulfide microspheres with crystalline Ni 3 S 2 intergrown in situ on Ni foam (MoO x S y /Ni 3 S 2 /NF) as an outstanding electrocatalyst for HER. The MoO x S y /Ni 3 S 2 /NF demonstrates an ultra-low overpotential of 58 mV at a current density of 10 mA cm -2 and extremely durable stability (>200 h), suggesting superior performance comparable to that of Pt-C/NF under acidic conditions. The X-ray absorption fine structure (XAFS) determines the average valence state of Mo to be +(5 + δ), with a coordination motif by O and S. To explain such high HER activity, a [Mo 2 O 2 (S,O) 4 ] dimer-based periodic model structure with the average composition of [Mo 4 O 8 S 4 ] interfaced with the Ni 3 S 2 (101) surface is proposed. The interactions between the Ni of Ni 3 S 2 and bridging S/O of [Mo 4 O 8 S 4 ] result in an average formal Mo charge state between +5 and +6, and significant charge transfer from Ni 3 S 2 to [Mo 4 O 8 S 4 ] activates the Mo = O bonds. The calculated |ΔG H* | of less than 50 meV suggests that the double-bonded O is the most active site. This work points to the importance of oxy/sulfides with Mon+ (+5 < n < +6) as exceptional electrochemical catalysts for HER.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2024

The protein structurome of Orthornavirae and its dark matter

Metatranscriptomics is uncovering more and more diverse families of viruses with RNA genomes comprising the viral kingdom Orthornavirae in the realm Riboviria. Thorough protein annotation and comparison are essential to get insights into the functions of viral proteins and virus evolution. In addition to sequence- and hmm profile-based methods, protein structure comparison adds a powerful tool to uncover protein functions and relationships. We constructed an Orthornavirae “structurome” consisting of already annotated as well as unannotated (“dark matter”) proteins and domains encoded in viral genomes. We used protein structure modeling and similarity searches to illuminate the remaining dark matter in hundreds of thousands of orthornavirus genomes. The vast majority of the dark matter domains showed either “generic” folds, such as single α-helices, or no high confidence structure predictions. Nevertheless, a variety of lineage-specific globular domains that were new either to orthornaviruses in general or to particular virus families were identified within the proteomic dark matter of orthornaviruses, including several predicted nucleic acid-binding domains and nucleases. In addition, we identified a case of exaptation of a cellular nucleoside monophosphate kinase as an RNA-binding protein in several virus families. Notwithstanding the continuing discovery of numerous orthornaviruses, it appears that all the protein domains conserved in large groups of viruses have already been identified. The rest of the viral proteome seems to be dominated by poorly structured domains including intrinsically disordered ones that likely mediate specific virus-host interactions.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2026

Evolution of the Antarctic Ice Sheet from 2000–2300 and beyond: model sensitivity and uncertainty analysis using MPAS-Albany Land Ice

We present a description of the Antarctic Ice Sheet model configuration submitted to the ISMIP6-Antarctica-2300 experiment using the MPAS-Albany Land Ice model, along with three new sets of simulations: (1) a set of extended simulations to 2500 for three forced experiments and to 2775 for the control experiment; (2) a sensitivity analysis of our model configuration to parameters controlling basal sliding and sub-shelf melt, and to model structural choices including the choice of the energy and stress balances; and (3) a 72-member ensemble run on graphics processing units (GPUs) and analysis of variance to determine the primary sources of uncertainty in our ice-sheet model projections. Our extended simulations predict rapid retreat beginning after 2300 for SSP1-2.6 forcing and after 2500 for present-day (control) forcing, primarily in the Amundsen Sea Embayment. We find that varying the sub-shelf melt parameter between the 5th to 95th percentile values for a mean-Antarctic calibration target results in an up to ∼ ± 40 % change in sea-level contribution relative to our baseline simulations that used the median value. Using a linear basal sliding law reduces sea-level contribution by 51 %–73 % relative to our baseline nonlinear sliding law with an exponent of 1/5. When using basal sliding law exponents of 1/3 and 1/10, the overall difference from our baseline simulations at 2300 is on the order of 10 %. The Amundsen Sea Embayment region displays a strongly non-linear dependence of mass loss on the sliding law exponent, with no discernible relationship between the sliding law exponent and the mass loss by 2300, while the sectors feeding the Ross and Filchner-Ronne ice shelves exhibit more mass loss with a more-plastic sliding law. Our model fidelity sensitivity experiments reveal a 9 %–31 % increase in sea-level contribution when using a depth-integrated stress balance approximation relative to our three-dimensional solver, while using a fixed-in-time temperature field increases sea-level contribution by 14 %–88 % relative to two thermomechanically coupled configurations. Our 72-member ensemble and analysis of variance show that the uncertainty in long-term projections is dominated by the choice of Earth system model forcing and the presence or absence of hydrofracture forcing, rather than uncertainty in sliding and sub-shelf melt parameters.

58 GEOSCIENCES↗

DOE OSTI2024

Exploring the Links between Structural Distortions, Orbital Ordering, and Multipolar Magnetic Ordering in Double Perovskites Containing Re(VI) and Os(VII)

A combination of high-resolution powder diffraction techniques and solid-state NMR has been employed to explore the links between crystal structure, orbital ordering, and magnetism in three isostructural double perovskites containing transition metal ions with a 5d 1 configuration. In Ba 2 ZnReO 6 , both neutron and synchrotron X-ray powder diffraction data reveal a cubic-to-tetragonal transition at 23 K that breaks the degeneracy of the t 2g orbitals and leads to a pattern of orbital ordering that stabilizes magnetic ordering when the sample is cooled below 16 K. Similar behavior is observed in Ba 2 MgReO 6 , with an orbital ordering temperature of 33 K and a magnetic ordering temperature of 18 K. Prior theoretical works suggest that the pattern of orbital order seen in the P42/mnm space group is needed to stabilize the heavily canted antiferromagnetism of these compounds. Unfortunately, powder diffraction data is not sensitive enough to differentiate between the I4/mmm and P42/mnm structural models, as the distortions are too subtle to be unambiguously identified from either neutron or synchrotron X-ray powder diffraction methods. In contrast, both diffraction and 7 Li NMR data indicate that Ba 2 LiOsO 6 retains the cubic structure down to 1.7 K. The antiferromagnetic ground state and lack of any sign of orbital ordering in Ba 2 LiOsO 6 provide compelling evidence that the electronically driven tetragonal distortion seen in Ba2ZnReO6, and Ba2MgReO6 is intimately linked to the magnetic ordering seen in those compounds. The absence of magnetic reflections in high intensity neutron powder diffraction data collected on Ba 2 MgReO 6 strongly suggests ordering of multipolar moments on Re(VI), likely ferro-octupolar ordering.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2024

NSTXU Diagnostic Disruption Dynamic Loading Represented by Response Spectra

This article presents the results of transient dynamic simulations of loads due to disruption eddy currents on the NSTXU vacuum vessel. Dynamic loading at diagnostic mounting locations is expressed as response spectra derived from the time history results of the dynamic structural simulations of a variety of disruption scenarios. The disruption simulations draw on a history of the project assessments of worst case disruptions for specific components. Major efforts to assess disruption loading have included the vacuum vessel which is the major structural support for the machine, as well as the passive plates (PPs), high harmonic fast wave (HHFW) antenna, and centerstack casing. Each one of these efforts included transient electromagnetic simulations producing time-dependent eddy current Lorentz loads (and in some cases halo loads) which then were applied to time-dependent structural dynamic analyses intended to obtain the proper dynamic amplification factors. In some instances, the EM model and structural model were identical allowing direct transfer of EM forces to the structural model. In other cases, the EM and structural model were not identical and the vector potential (VP) transfer method was used. The results files from these analyses were available (or re-run) to post process in ANSYS Classic time history postprocessor. In conclusion, the ANSYS command is used to create response spectra from time history data at desired points on the vessel.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

DOE OSTI2015

Coupling fracture facies with in-situ permeability measurements to generate stochastic simulations of tight carbonate aquifer properties: Example from the Lower Cretaceous aquifer, Northern Provence, SE France

The relationships between fracture facies and permeability distribution have been explored using a well-constrained 3D implicit structural model of hemipelagic low porosity/low permeability carbonate from the Northern Provence region, SE France. Fracture and permeability facies were determined using an extensive dataset of 99 hydrogeological wells. Data processing was undertaken using a step-by-step approach, involving: (i) identification of the fracture facies based on well logs detailing structure and stratigraphy; (ii) determination of permeability facies from the a priori correlation between the dimension of the hydraulic radius of influence (deduced from slug test analyses) and the type of reservoir heterogeneity (fissure, fracture, fault zone, etc.); (iii) three dimensional plot of fracture and permeability facies in the geological model using a variographic analysis of data. Thirty-three sequential indicator simulations (SIS) based on geostatistic analyses were realised on both fracture and permeability facies. Finally, a connectivity algorithm was developed to compute the probability of connection between selected infiltration areas and the major aquifer springs via moderate- to high-permeability geological bodies. Key results are: (i) fault zones have a greater role in controlling permeability facies distribution than on fracture facies repartition; (ii) there is little correlation between permeability and fracture facies distributions; (iii) connectivity results highlight the compartmentalisation of aquifers in the Cadarache area, the extensions of permeable geological bodies being limited by the N130 faults.

58 GEOSCIENCES↗

DOE OSTI2022

Exploring cryo-electron microscopy with molecular dynamics

Single particle analysis cryo-electron microscopy (EM) and molecular dynamics (MD) have been complimentary methods since cryo-EM was first applied to the field of structural biology. The relationship started by biasing structural models to fit low-resolution cryo-EM maps of large macromolecular complexes not amenable to crystallization. The connection between cryo-EM and MD evolved as cryo-EM maps improved in resolution, allowing advanced sampling algorithms to simultaneously refine backbone and sidechains. Moving beyond a single static snapshot, modern inferencing approaches integrate cryo-EM and MD to generate structural ensembles from cryo-EM map data or directly from the particle images themselves. We summarize the recent history of MD innovations in the area of cryo-EM modeling. The merits for the myriad of MD based cryo-EM modeling methods are discussed, as well as, the discoveries that were made possible by the integration of molecular modeling with cryo-EM. Lastly, current challenges and potential opportunities are reviewed.

Biochemistry & Molecular Biology↗

DOE OSTI2019

In Quest of Calibration Density and Consistency in Hydrologic Modeling: Distributed Parameter Calibration against Streamflow Characteristics

Conventional basin-by-basin approaches to calibrate hydrologic models are limited to gauged basins and typically result in spatially discontinuous parameter fields. Moreover, the consequent low calibration density in space falls seriously behind the need from present-day applications like high resolution river hydrodynamic modeling. In this study we calibrated three key parameters of the Variable Infiltration Capacity (VIC) model at every 1/8° grid-cell using machine learning-based maps of four streamflow characteristics for the conterminous United States (CONUS), with a total of 52,663 grid-cells. This new calibration approach, as an alternative to parameter regionalization, applied to ungauged regions too. A key difference made here is that we tried to regionalize physical variables (streamflow characteristics) instead of model parameters whose behavior may often be less well understood. The resulting parameter fields no longer presented any spatial discontinuities and the patterns corresponded well with climate characteristics, such as aridity and runoff ratio. The calibrated parameters were evaluated against observed streamflow from 704/648 (calibration/validation period) small-to-medium-sized catchments used to derive the streamflow characteristics, 3941/3809 (calibration/validation period) small-to-medium-sized catchments not used to derive the streamflow characteristics as well as five large basins. Comparisons indicated marked improvements in bias and Nash-Sutcliffe efficiency. Model performance was still poor in arid and semiarid regions, which is mostly due to both model structural and forcing deficiencies. Although the performance gain was limited by the relative small number of parameters to calibrate, the study and results here served as a proof-of-concept for a new promising approach for fine-scale hydrologic model calibrations.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2020

From pools to flow: The PROMISE framework for new insights on soil carbon cycling in a changing world

Soils represent the largest terrestrial reservoir of organic carbon, and the balance between soil organic carbon (SOC) formation and loss will drive powerful carbon-climate feedbacks over the coming century. To date, efforts to predict SOC dynamics have rested on pool-based models, which assume classes of SOC with internally homogenous physicochemical properties. However, emerging evidence suggests that soil carbon turnover is not dominantly controlled by the chemistry of carbon inputs, but rather by restrictions on microbial access to organic matter in the spatially heterogeneous soil environment. The dynamic processes that control the physicochemical protection of carbon translate poorly to pool-based SOC models; as a result, we are challenged to mechanistically predict how environmental change will impact movement of carbon between soils and the atmosphere. In this study, we propose a novel conceptual framework to explore controls on belowground carbon cycling: Probabilistic Representation of Organic Matter Interactions within the Soil Environment (PROMISE). In contrast to traditional model frameworks, PROMISE does not attempt to define carbon pools united by common thermodynamic or functional attributes. Rather, the PROMISE concept considers how SOC cycling rates are governed by the stochastic processes that influence the proximity between microbial decomposers and organic matter, with emphasis on their physical location in the soil matrix. We illustrate the applications of this framework with a new biogeochemical simulation model that traces the fate of individual carbon atoms as they interact with their environment, undergoing biochemical transformations and moving through the soil pore space. We also discuss how the PROMISE framework reshapes dialogue around issues related to SOC management in a changing world. We intend the PROMISE framework to spur the development of new hypotheses, analytical tools, and model structures across disciplines that will illuminate mechanistic controls on the flow of carbon between plant, soil, and atmospheric pools.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2020

Combining Three-Dimensional Modeling with Artificial Intelligence to Increase Specificity and Precision in Peptide–MHC Binding Predictions

The reliable prediction of the affinity of candidate peptides for the MHC is important for predicting their potential antigenicity and thus influences medical applications, such as decisions on their inclusion in T cell–based vaccines. In this study, we present a rapid, predictive computational approach that combines a popular, sequence-based artificial neural network method, NetMHCpan 4.0, with three-dimensional structural modeling. We find that the ensembles of bound peptide conformations generated by the programs MODELLER and Rosetta FlexPepDock are less variable in geometry for strong binders than for low-affinity peptides. In tests on 1271 peptide sequences for which the experimental dissociation constants of binding to the well-characterized murine MHC allele H-2D b are known, by applying thresholds for geometric fluctuations the structure-based approach in a standalone manner drastically improves the statistical specificity, reducing the number of false positives. Furthermore, filtering candidates generated with NetMHCpan 4.0 with the structure-based predictor led to an increase in the positive predictive value (PPV) of the peptides correctly predicted to bind very strongly (i.e., Kd < 100 nM) from 40 to 52% (p = 0.027). The combined method also significantly improved the PPV when tested on five human alleles, including some with limited data for training. Overall, an average increase of 10% in the PPV was found over the standalone sequence-based method. The combined method should be useful in the rapid design of effective T cell–based vaccines.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Alzheimer's Aβ 1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product

The interaction of the amyloid‐β peptide (Aβ) with thermolysin ( TLN ) was investigated by X‐ray crystallography. Structural models of the complexes of TLN with several Aβ fragments show that, despite the numerous possible cleavage sites of the Aβ sequence, the C‐terminal product of Ala30‐Ile31 cleavage does not dissociate, thus inhibiting the enzyme. The high similarity between the TLN structural motif and neprilysin ( NEP ), the most extensively studied peptidase associated with Aβ clearance, suggests that NEP should be more efficient against Aβ polymorphs where Ala30‐Ile31 is inaccessible, which is in agreement with studies in living mice that point to the limited role of NEP in degrading soluble Aβ and its higher ability to degrade insoluble and/or oligomeric Aβ forms, producing only the Aβ 10–37 intermediate.

Leite, José P.↗

DOE OSTI2025

Predicting receptor-ligand pairing preferences in plant-microbe interfaces via molecular dynamics and machine learning

Microbiome assembly, structure, and dynamics significantly influence plant health. Secreted microbial signaling molecules initiate and mediate symbiosis by binding to structurally compatible plant receptors. For example, lipo-chitooligosaccharides (LCOs), produced by nitrogen-fixing rhizobial bacteria and various fungi, are recognized by plant lysin motif receptor-like kinases (LysM-RLKs), which activate the common symbiotic pathway. Accurately predicting these molecular interactions could reveal complementary signatures underlying the initial stages of endosymbiosis. Despite the breakthrough in protein-ligand structure prediction with deep learning-based tools, such as AlphaFold3, the large size and highly flexible nature of signaling compounds like LCOs present major challenges for detailed structural characterization and binding-affinity prediction. Typical structure-/physics-based methods of ligand virtual screening are designed for small, drug-like molecules, often rely on high-resolution, experimentally determined structures of the protein receptors, and rarely achieve sufficient sampling to obtain converged thermodynamic quantities with large ligands. In this study, we developed a hybrid molecular dynamics/machine learning (MD/ML) approach capable of predicting binding affinity rankings with high accuracy in systems involving large, flexible ligands, despite limited experimental structural information. Using coarse initial structural models, the predictions using the MD/ML workflow achieved strong alignment with experimental trends, particularly in the top-affinity tier for four legume LysM-RLKs (LYR3) binding to LCOs and a chitooligosaccharide. Furthermore, the MD-based conformation selection protocol provided critical structural insights into substrate specificity and binding mechanisms. This study demonstrates a powerful method to screen for challenging cognate ligand-receptors and advance our understanding of the molecular basis of microbial colonization in plants.

Lipo-chitooligosaccharides↗