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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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All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Structure of a biohybrid photosystem I-platinum nanoparticle solar fuel catalyst

Biohybrid solar fuel catalysts leverage natural light-driven enzymes to produce valuable fuel products. One useful biological platform for such a system is photosystem I, a pigment-protein complex that captures sunlight and converts it into chemical energy with near unity quantum efficiency, which generates low potential reducing equivalents for metabolism. Realizing and understanding the molecular basis for an approach that utilizes those electrons and stores solar energy as a fuel is therefore appealing. Here, we report the 2.27-Å global resolution cryo-EM structure of a photosystem I complex with bound platinum nanoparticles that catalyzes light-driven H 2 production. The platinum nanoparticle binding sites and possible stabilizing interactions are described. Overall, the investigation reveals a direct structural look at a photon-to-fuels photosynthetic biohybrid system.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Building molecular model series from heterogeneous CryoEM structures using Gaussian mixture models and deep neural networks

Cryogenic electron microscopy (CryoEM) produces structures of macromolecules at near-atomic resolution. However, building molecular models with good stereochemical geometry from those structures can be challenging and time-consuming, especially when many structures are obtained from datasets with conformational heterogeneity. Here we present a model refinement protocol that automatically generates series of molecular models from CryoEM datasets, which describe the dynamics of the macromolecular system and have near-perfect geometry scores. This method makes it easier to interpret the movement of the protein complex from heterogeneity analysis and to compare the structural dynamics observed from CryoEM data with results from other experimental and simulation techniques.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Progress in the development of an ultrafast pulsed ponderomotive phase plate for cryo-electron tomography

Cryo-electron tomography (cryo-ET) is a powerful modality for resolving cellular structures in their native state. While single-particle cryo-electron microscopy excels in determining protein structures purified from recombinant or endogenous sources due to an abundance of particles, weak contrast issues are accentuated in cryo-ET by low copy numbers in crowded cellular milieux. Continuous laser phase plates offer improved contrast in cryo-ET; however, their implementation demands exceptionally high-peak optical intensities. Instead, a novel experimental approach to enhance contrast in cryo-ET is to manipulate the phase of scattered pulsed electrons using ultrafast pulsed photons. Here, we outline the experimental design of a proof-of-concept electron microscope and demonstrate synchronization between electron packets and laser pulses. Furthermore, we show ultrabright photoemission of electrons from an alloy field emission tip using femtosecond ultraviolet pulses. These experiments pave the way toward exploring the utility of the ponderomotive effect using pulsed radiation to increase phase contrast in cryo-ET of subcellular protein complexes in situ, thus advancing the field of cell biology.

Du, Daniel X. [Columbia Univ., New York, NY (Unite↗
DOE OSTI2024

The interplay of excitonic delocalization and vibrational localization in optical lineshapes: A variational polaron approach

The dynamics of molecular excitonic systems are complicated by a competition between electronic coupling (which drives delocalization) and vibrational-electronic (vibronic) interactions (which tend to encourage electronic localization). A particular challenge of molecular systems is that they typically possess a large number of independent vibrations, with frequencies often spanning the entire spectrum of relevant electronic energy gaps. Recent spectroscopic observations and numerical simulations on a water-soluble chlorophyll-binding protein (WSCP) reveal a transition between two regimes of vibronic behavior, a Redfield-like regime in which low-frequency vibrations respond to a delocalized excitonic state, and a Förster-like regime where high-frequency vibrations act as incoherent excitations on individual pigments. Although numerical simulations can reproduce these effects, there is a need for a simple, systematic theory that accurately describes the smooth transition between these two regimes in experimental spectra. Here we address this challenge by generalizing the variational polaron transform approach of [Bloemsma et al., Chem. Phys. 481, 250 (2016)] to include arbitrary bath densities for systems with or without symmetry. We benchmark this theory against both numerical matrix-diagonalization methods and experimental 77 K fluorescence spectra for two WSCP variants, obtaining quite satisfactory agreement in both cases. Here, we apply this theory to offer an explanation for the large loss in apparent electronic coupling in the WSCP Q57K mutant and to examine the likely impact of the interplay between excitonic delocalization and vibrational localization on vibrational sideband shapes and apparent coupling strengths in high-resolution optical spectra for chlorophyll-protein complexes such as WSCP.

14 SOLAR ENERGY↗
DOE OSTI2025

Database of low‐temperature absorption and fluorescence spectra of native photosynthetic tetrapyrrole macrocycles

Low-temperature (77 K) absorption and fluorescence spectra of 12 naturally occurring photosynthetic tetrapyrrole macrocycles have been recorded in a frozen glass (2-methyltetrahydrofuran). The compounds encompass distinct chromophore classes: porphyrin, chlorophyll c 2 ; chlorin, chlorophylls a, b, d, f and bacteriochlorophylls c, d, e, f; and bacteriochlorin, bacteriochlorophylls a, b, g. The spectra are compared with those of the same pigment in liquid solution (predominantly 2-methyltetrahydrofuran) at room temperature (293 K). The measured Stokes shifts at 77 K across the 12 macrocycles range from ~30 to 300 cm −1 . The spectral data in digital form are made available as part of the PhotochemCAD databases. Literature searches have revealed extensive published data for Chl a (often in biological matrices) but at best rather limited data for less common macrocycles. The availability of a systematic collection of curated spectral data collected at low temperature should be useful for a variety of assessments, including reconstruction of absorption spectra of (bacterio)chlorophyll-containing protein complexes, vibrational analysis of absorption and fluorescence spectra, and calculations where knowledge of energy levels is important.

Niedzwiedzki, Dariusz M. [Washington University in↗
DOE OSTI2025

Modeling Protein–Protein and Protein–Ligand Interactions by the ClusPro Team in CASP16

ABSTRACT In the CASP16 experiment, our team employed hybrid computational strategies to predict both protein–protein and protein–ligand complex structures. For protein–protein docking, we combined physics‐based sampling—using ClusPro FFT docking and molecular dynamics—with AlphaFold (AF)‐based sampling, followed by AF‐based refinement. Our method produced numerous high‐accuracy complex models, including cases where AF alone failed, underscoring the critical role of physics‐based sampling alongside deep learning‐based refinement. For protein–ligand docking, we integrated the ClusPro LigTBM template‐based approach with a machine learning‐based confidence model for rescoring. The method preserves conserved interaction fragments derived from homologous complexes, followed by local resampling using physics‐based sampling and a diffusion model. Our template‐based strategy achieved a mean lDDT‐PLI of 0.69 across 233 targets, which was highly competitive. These results demonstrate that combining physics‐based modeling with AI‐driven refinement can significantly enhance the accuracy of both protein–protein and protein–ligand structure predictions.

Ashizawa, Ryota [Department of Applied Mathematics↗
DOE OSTI2025

Predicting metal-binding proteins and structures through integration of evolutionary-scale and physics-based modeling

Metals are essential elements in all living organisms, binding to approximately 50% of proteins. They serve to stabilize proteins, catalyze reactions, regulate activities, and fulfill various physiological and pathological functions. While there have been many advancements in determining the structures of protein-metal complexes, numerous metal-binding proteins still need to be identified through computational methods and validated through experiments. Here, to address this need, we have developed the ESMBind workflow, which combines evolutionary scale modeling (ESM) for metal-binding prediction and physics-based protein-metal modeling. Our approach utilizes the ESM-2 and ESM-IF models to predict metal-binding probability at the residue level. In addition, we have designed a metal-placement method and energy minimization technique to generate detailed 3D structures of protein-metal complexes. Our workflow outperforms other models in terms of residue and 3D-level predictions. To demonstrate its effectiveness, we applied the workflow to 142 uncharacterized fungal pathogen proteins and predicted metal-binding proteins involved in fungal infection and virulence.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

CHARMM-GUI Bicelle Builder : An Extension of Membrane Builder for Modeling and Simulation of Bicelle Systems

Membrane mimetics, such as detergent micelles, nanodiscs, and amphipol complexes, which can provide membrane-like environments while retaining small and soluble features, have been utilized to study membrane proteins. A bicelle, composed of varying lipids and detergents, is a useful membrane mimetic because the lipid-to-detergent ratio, the q-value, can be adjusted to alter the properties of the aggregate, including the thickness and size of the bicelle. However, building a bicelle model for modeling and simulation studies requires nontrivial efforts, even for experts. We introduce CHARMM-GUI Bicelle Builder, a web-based platform that can generate various all-atom bicelle systems via a graphical user interface with all available lipids and detergents in Membrane Builder. To illustrate and validate Bicelle Builder with practical systems, we have modeled and simulated pure bicelles consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipids with 1,2-dihexanoyl-sn-glycero-3-phosphocholine (C6DHPC) detergents and protein–bicelle complexes, composed of DMPC with C6DHPC, foscholine-10 (FOS10), and lysophosphatidylcholine-12 (LPC12) detergents. Our simulation results indicate that Bicelle Builder can generate reliable and robust bicelle models with and without proteins that retain DMPC bilayer characteristics. Bicelle Builder is expected to help researchers better understand not only bicelles themselves but also atomistic-level structures of protein–bicelle complexes that are often difficult to access through experimental approaches.

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

Equivariant Graph Attention Network - 3D Conformers & Feature Fusion

EGAN-3F (Equivariant Graph Attention Network - 3D Conformers & Feature Fusion) presents an innovative approach for predicting binding affinity between small molecules and protein targets, a fundamental task in drug discovery. Traditional structure-based methods often depend on protein-ligand complex structures obtained from crystallography or molecular docking. In contrast, ligand-only machine learning models using 1D or 2D representations such as SMILES have been developed to predict binding affinity without structural information about the target; however, their accuracy is often limited due to the lack of 3D ligand information. EGAN-3F addresses this limitation by integrating spatially aware graph learning with traditional descriptor-based features. We systematically investigate how combining 2D and 3D molecular representations enhances binding affinity prediction from SMILES strings. This approach underscores the importance of modeling conformational diversity and incorporating chemically meaningful descriptors to improve predictive accuracy. The key innovation of EGAN-3F lies in its ability to achieve robust ligand-based binding affinity predictions without requiring protein-ligand complex structures, effectively bridging the gap between purely structural and ligand-only modeling paradigms.

Shim, Heesung [Lawrence Livermore National Laborat↗
DOE OSTI2026

Identification of drug repurposing candidates for amyotrophic lateral sclerosis using electronic health records: a retrospective cohort study

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a life expectancy of only 3–5 years and few approved treatments. To identify drug repurposing candidates for the treatment of ALS, we analysed the electronic health records (EHRs) of a large cohort of military veterans with ALS. We analysed the EHRs of individuals in the US Veterans Health Administration (VHA) database who were diagnosed with ALS between Jan 1, 2009 and Dec 31, 2019 to assess medication effects. Individuals without recorded prescriptions after the date of diagnosis were excluded. Two sets of criteria were applied to ascertain exposure. Exposure criteria A were met if the dispense date or the end date of the medication was within 12 months of ALS diagnosis and the end date was at least 6 months after the dispense date. Exposure criteria B were met if there were at least two dispenses within 6 months before diagnosis and 12 months after diagnosis. Propensity score-matched control groups were generated on the basis of confounders included in the EHR, with methodology of potential outcomes used to infer treatment effects. The primary outcome was death. A standard Cox proportional hazards analysis was done to assess association with survival. Survival was defined as the time from diagnosis date recorded in the EHR to death reported in the Department for Veterans Affairs Vital Status File. Follow-up survival time was censored on Dec 31, 2020, for those alive on this date. Downstream protein targets of drugs with clinically significant effects were analysed using the protein–protein interaction networks-based algorithm PathFX. The EHRs of 11 003 individuals with ALS in the VHA database were appropriate for analysis. 162 medications with treatment groups of 30 or more individuals were identified. Among these 162 medications, 27 were associated with statistically significant changes (≥0·1) in the hazard ratio (HR) for death. 18 of the medications were associated with a reduced HR for death (prolonged survival), and nine were associated with an increased HR for death (reduced survival). Drugs associated with reduced HR included HMG-CoA reductase inhibitors (simvastatin, pravastatin, lovastatin, and atorvastatin), PDE5 inhibitors (vardenafil and sildenafil), and α-adrenergic antagonists (tamsulosin and terazosin). The medications associated with an increased HR were drugs used either in the management of clinical features of ALS associated with poor outcomes or in end-of-life care. PathFx analysis identified a complex of proteins interacting with several of the identified drugs. To our knowledge, this analysis is the largest EHR-based study for identifying drug repurposing candidates for ALS. We identified several drugs that warrant further assessment as therapeutic options in ALS, as well as a protein network complex that might serve as a therapeutic target for ALS.

Reimer, Richard J. [Stanford Univ., CA (United Sta↗
DOE OSTI2025

From cytoplasm to lumen—mapping the free pools of protein subunits of three photosynthetic complexes using quantitative mass spectrometry

The phycobilisome (PBS) captures light energy and transfers it to photosystem I (PSI) and photosystem II (PSII). Which and how many copies of protein subunits in PBSs, PSI, and PSII remain unbound in thylakoids are unknown. Here, quantitative mass spectrometry (QMS) was used to quantify substantial pools of free extrinsic subunits of PSII and PSI. Interestingly, the membrane intrinsic PsaL is 3-fold higher than PsaA/B. This scenario complements the static structures of these complexes as revealed by X-ray crystallography and cryo-EM. Furthermore, the ratios of ApcG and photoprotective OCP over PBS indicate a pool of extra ApcG. The 2.5 ratio of CpcG-PBS over CpcL-PBS improves our understanding of these light-harvesting complexes involved in energy capture and photoprotection in cyanobacteria.

cyanobacteria↗
DOE OSTI2026

Structural Heterogeneity and Hydrodynamics of an Intrinsically Disordered Protein Condensate

Biology demonstrates precise control over the free-energy landscape through the selective partitioning of biomacromolecules into membraneless organelles, enabling essential functions such as biochemical transformations, signaling cascades, and mechanical reinforcement. Although the function of these condensates depends on their underlying structure and hydrodynamics, molecular-scale information on these systems remains sparse. Here, in this study, neutron scattering is used to probe the organization and dynamics of the intrinsically disordered N-terminal domain of Galectin-3, an extracellular lectin responsible for facilitating liquid–liquid phase separation on the cellular surface, in both dilute and condensed phases. Dilute solutions contain isolated protein chains in equilibrium with mesoscopic clusters, whereas the condensed phase adopts a bicontinuous, microemulsion-like morphology. The dilute phase behavior is quantitatively described by coarse-grained polymer models from soft-matter physics, demonstrating their predictive power for complex biological proteins. At elevated concentrations, the proteins self-assemble akin to block copolymers, microphase separating through the aggregation of hydrophobic domains along the protein contour. The resulting condensate remains fluid-like despite a 25-fold increase in concentration; its internal hydrodynamics slow by only a factor of 3 relative to dilute protein chains. These results provide a molecular-level framework for how disordered proteins achieve both the structural complexity and dynamic fluidity of biomolecular condensates.

Carrick, Brian R. [Massachusetts Inst. of Technolo↗
DOE OSTI2024

VPS26 Moonlights as a β-Arrestin-like Adapter for a 7-Transmembrane RGS Protein in Arabidopsis thaliana

Extracellular signals perceived by 7-transmembrane (7TM)-spanning receptors initiate desensitization that involves the removal of these receptors from the plasma membrane. Agonist binding often evokes phosphorylation in the flexible C-terminal region and/or intracellular loop 3 of many 7TM G-protein-coupled receptors in animal cells, which consequently recruits a cytoplasmic intermediate adaptor, β-arrestin, resulting in clathrin-mediated endocytosis (CME) and downstream signaling such as transcriptional changes. Some 7TM receptors undergo CME without recruiting β-arrestin, but it is not clear how. Arrestins are not encoded in the Arabidopsis thaliana genome, yet Arabidopsis cells have a well-characterized signal-induced CME of a 7TM protein, designated Regulator of G Signaling 1 (AtRGS1). Here we show that a component of the retromer complex, Vacuolar Protein Sorting-Associated 26 (VPS26), binds the phosphorylated C-terminal region of AtRGS1 as a VPS26A/B heterodimer to form a complex that is required for downstream signaling. We propose that VPS26 moonlights as an arrestin-like adaptor in the CME of AtRGS1.

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

Driving Electron Transfer in Photosystem I Using Far-Red Light: Overall Perspectives

Photosystem I (PSI) is a photosynthetic protein–pigment complex that, upon photoexcitation, transfers electrons to ferredoxin, facilitating the production of NADPH. Isolated PSI reaction centers (RCs) have also been used in hybrid systems to reduce protons and produce ‘biohydrogen’. This review article examines how various cyanobacteria with similar photosynthetic machinery utilize different wavelengths of light to execute photosynthetic electron transport through PSI. Key factors, such as, the structure of the electron transfer cofactors, the protein environment surrounding the primary donor pigments and hydrogen-bonding interactions with the surrounding protein matrix are analyzed to understand their roles in maintaining efficient electron transfer when it is driven using photons of different energies. We compare PSI complexes with known atomic structures from four species of cyanobacteria, Thermosynechococcus elongatus, Acaryochloris marina, Halomicronema hongdechloris, and Fischerella thermalis. T. elongatus is typical of most oxygenic photosynthetic organisms in that it requires visible light and uses only chlorophyll a (Chl a ) in PSI. In contrast, H. hongdechloris and F. thermalis are photoacclimating species capable of producing Chl f and Chl d that use red light when little visible light is available. A. marina , on the other hand, is adapted to red light conditions and consistently utilizes Chl d as its primary photosynthetic pigment, maintaining a stable pigment composition. Here, we explore the structural and functional differences between the PSI RCs of these organisms and the impact of these differences on electron transport. The structural differences in the cofactors influence both the absorption wavelengths of the cofactors and the energy levels of the intermediate states of electron transfer. An analysis of the surrounding protein shows how it has been adapted and underscores the interplay between the pigment structure, protein environment, and hydrogen bonding networks in tuning the efficiency and adaptability of photosynthetic mechanisms across different species of cyanobacteria.

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

Structural studies of the IFNλ4 receptor complex using cryoEM enabled by protein engineering

Abstract IFNλ4 has posed a conundrum in human immunology since its discovery in 2013, with its expression linked to complications with viral clearance. While genetic and cellular studies revealed the detrimental effects of IFNλ4 expression, extensive structural and functional characterization has been limited by the inability to express and purify the protein, complicating explanations of its paradoxical behavior. In this work, we report a method for robust production of IFNλ4. We then use yeast surface display to affinity-mature IL10Rβ and solve the 72 kilodalton structures of IFNλ4 (3.26 Å) and IFNλ3 (3.00 Å) in complex with their receptors IFNλR1 and IL10Rβ using cryogenic electron microscopy. Comparison of the structures highlights differences in receptor engagement and reveals a distinct 12-degree rotation in overall receptor geometry, providing a potential mechanistic explanation for differences in cell signaling, downstream gene induction, and antiviral activities. Further, we perform a structural analysis using molecular modeling and simulation to identify a unique region of IFNλ4 that, when replaced, enables secretion of the protein from cells. These findings provide a structural and functional understanding of the IFNλ4 protein and enable future comprehensive studies towards correcting IFNλ4 dysfunction in large populations of affected patients.

Science & Technology - Other Topics↗
DOE OSTI2025

Dynamics and lipid membrane coupling of the RAS-RAF complex revealed via multiscale simulations

To gain molecular and mechanistic insights into initiation of the RAS-RAF signaling cascade, we developed and used a combination of multiscale simulation and experimental approaches. The influence and impact of the membrane on RAS and RAF proteins is a factor we are just beginning to understand and appreciate in more detail. Molecular simulation is an ideal methodology to further study this complicated relationship between the membrane and associated proteins. Our previous work using Multiscale Machine-learned Modeling Infrastructure investigated different lipid compositions solely around the KRAS4b protein and the interplay between protein behavior and these membrane environments. Multiscale Machine-learned Modeling Infrastructure uses machine learning to couple adjacent simulation scales and has been efficiently scaled across some of the world’s largest high-performance computers. Recently, we have expanded this multiresolution framework to include the all-atom simulation scale and to incorporate the RAF RBDCRD domains. Here, we present the overall analysis results from this new simulation campaign comprising a mixture of RAS and RAF RBDCRD proteins. Approximately 35,000 coarse-grained and 10,000 all-atom molecular dynamics simulations were completed, sampled from a variety of protein/lipid composition configurations that were generated from a micron-scale continuum simulation containing hundreds of copies of the proteins. Our studies suggest that orientations of the RAS-RBDCRD complex on the membrane occupy distinct configurational states, and the spatial patterns of lipid arrangements around these different protein states are unique to each state. The extent and size of lipid “fingerprints” imposed on the membrane by the RAS-RBDCRD protein complex are significantly larger than observed for just the RAS protein on its own. These protein complexes strongly associate, but we do not observe statistically significant preferred protein-protein orientations. These observations indicate that spatial colocalization of RAS-RBDCRD proteins in the same vicinity may be assisted by specific membrane environments, acting to increase the probability of signaling complex formation.

Carpenter, Timothy S. [Lawrence Livermore National↗
DOE OSTI2025

Mining Thermophile Photosynthesis Genes: A Synthetic Operon Expressing Chloroflexota Species Reaction Center Genes in Rhodobacter sphaeroides

Photosynthesis is the foundation of the vast majority of life systems, and is therefore the most important bioenergetic process on earth. The greatest diversity of photosynthetic systems is found in microorganisms. However, our understanding of the biophysical and biochemical processes that transduce light into chemical energy is derived from a relatively small subset of proteins from microbes that are amenable to cultivation, in contrast to the huge number of predicted proteins that catalyze the initial photochemical reactions deposited in databases, such as from metagenomics. We describe the use of a Rhodobacter sphaeroides laboratory strain for the expression of heterologous photosynthesis genes to demonstrate the feasibility of mining this resource, focusing on hot spring Chloroflexota gene sequences. Using a synthetic operon of genes, we produced a photochemically active complex of reaction center proteins in our biological system. We also present bioinformatic analyses of anoxygenic type II reaction center sequences from metagenomic samples collected from hot (42–90 °C) springs available through the JGI IMG database, to generate a resource of diverse sequences that are potentially adapted to photosynthesis at such temperatures. These data provide a view into the natural diversity of anoxygenic photosynthesis, through a lens focused on high-temperature environments. The approach we took to express such genes can be applied for potential biotechnology purposes as well as for studies of fundamental catalytic properties of these heretofore inaccessible protein complexes.

Chloroflexota↗
DOE OSTI2025

Inter-cofactor protein remodeling rewires short-circuited transmembrane electron transfer

Intraprotein electron transfer (ET) requires explicit local control of the environment of cofactors to influence their intermolecular distances, relative orientations, and redox properties. Efficient, longer-range ET often utilizes molecular orbitals of aromatic residues present in the intervening space. Here, revitalization of a vestigial ET pathway in the bacterial photosynthetic reaction center is achieved by scanning with tryptophans to uncover markedly improved routes of electron conduction in a key stabilizing step spanning 15 Å between tetrapyrrole and quinone cofactors. This ET event is maximally enhanced by pairing one or more tryptophans with a threonine to influence quinone binding and/or redox potential. Synergistic effects of these substitutions increase the yield of that ET step to ~95%. Joining these substitutions with mutant residues that improve initial ET steps dramatically enhances transmembrane charge separation via this redesigned version of a pathway that is quantitatively inactive in the native protein-cofactor complex.

Biophysical chemistry↗