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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Dynamical Signatures of Thermotoga maritima Maltose-Binding Proteins Affected by Ligand Binding

Functional segregation among protein isoforms depends on the interplay of their overall structures and the molecular dynamics of these structures. Thermotoga maritima maltose-binding protein (tmMBP) isoforms show size-dependent differential binding of maltose and malto-oligomers while maintaining remarkable fold conservation. This differential behavior needs detailed characterization in native-like aqueous conditions to understand the effects of protein dynamics on ligand binding and recognition. Small-angle neutron scattering (SANS), neutron spin echo (NSE) spectroscopy, and dynamic light scattering (DLS) were used in conjunction with previously published computational molecular dynamics (MD) simulations to understand the dynamic behavior of tmMBPs experimentally. SANS provided information on the overall structure of the molecules, while NSE was used to determine the dynamics in the nanosecond time scale. Both tmMBP2 and tmMBP3 have a bidomain architecture linked with a flexible hinge, with the binding pocket sitting in the cleft between the two domains. tmMBP2 and tmMBP3 showed different solution dynamics, with the translational and rotational components dominating the dynamics of both systems, resulting in a clear differentiation of their diffusion pattern. A faster dynamics component was also observed and was attributed to segmental dynamics. Differences observed between the ligand-free (apo) and ligand-bound (holo) states of the two proteins are attributed to conformational entropy. Our results highlight the intricacies of how structure and dynamics can together shape binding to a repertoire of substrates in structurally similar proteins.

Diffusion↗
DOE OSTI2026

Single-Molecule Electron Transport in Peptoids

Peptoids are structural analogs of peptides in which side chains are appended to the backbone nitrogen rather than the α-carbon. The sequence-defined modularity of peptoids enables precise control over structure−function relationships, enabling applications in energy storage and biomedical materials. Despite recent progress, the role of sequence and conformation on electron transport in peptoid molecules is not fully understood. Here, we synthesize a library of peptoid oligomers and characterize their molecular electronic properties using the scanning tunneling microscope-break junction (STM-BJ) technique. Our results show well-defined electron transport behavior for peptoid sequences containing aromatic side groups lacking hydrogen bonds (H-bonds) and without chemical substitutions at the N−C α position. This behavior fundamentally differs from electron transport in peptides, where H-bond interactions give rise to higher conductance states. All-atom molecular dynamics (MD) simulations are used to understand the conformational heterogeneity of peptoids, and molecular conformations obtained from MD simulations are used in quantum mechanical calculations based on the nonequilibrium Green’s function−density functional theory (NEGF-DFT) formalism. In all cases, computational results are in reasonable qualitative agreement with experiments. Our work demonstrates that the conductance behavior of peptoids depends on monomer identity, including side-chain aromaticity and substitution at the N−C α position. Overall, this work provides new insights into the structure−function relationships governing electron transport in peptoid-based materials and establishes design rules for peptoid-based molecular junctions.

Charge transport↗
DOE OSTI2025

Determining the Conformation of Supported Complexes Using an 17 O TEDOR-like NMR Experiment

Dynamic nuclear polarization surface-enhanced nuclear magnetic resonance (NMR) spectroscopy has enabled the determination of the three-dimensional configuration of surface sites, in particular supported metal complexes of relevance to single-site heterogeneous catalysis. These approaches have chiefly leveraged the application of NMR double-resonance experiments that either reveal the complex conformation via point-to-point intramolecular distances between spin-labeled atoms or the complex-surface orientation via distances between the spins and the surface plane. Either method typically requires expensive isotope labeling and each reports on different structural features. The application of an experiment that simultaneously reveals both types of distances with chemical resolution would be ideal. Here, in this article, we describe an 17 O{ 1 H} pseudo-3D correlation experiment that achieves this goal. Specifically, Si–O–Si and Si–O–M oxygens are well-resolved by 17 O NMR; therefore, distances can be simultaneously measured radially, between Si– 17 O–M and the 1 H’s of the ligands, and vertically to the Si– 17 O–Si linkages of the silica support. We demonstrate the experiment using supported yttrium and zirconium complexes. Good agreement is obtained when comparing the experimental results to theoretical predictions from density functional theory calculations, highlighting the reliability of this relatively simple experiment.

alkyls↗
NASA NTRS2010

Interactions of Ku70/80 with Double-Strand DNA: Energetic, Dynamics, and Functional Implications

Space radiation is a proficient inducer of DNA damage leading to mutation, aberrant cell signaling, and cancer formation. Ku is among the first responding proteins in nucleus to recognize and bind the DNA double strand breaks (DSBs) whenever they are introduced. Once loaded Ku works as a scaffold to recruit other repair factors of non-homologous end joining and facilitates the following repair processes. The crystallographic study of the Ku70/80 heterodimer indicate the core structure of this protein shows virtually no conformational change after binding with DNA. To investigate the dynamical features as well as the energetic characteristics of Ku-DNA binding, we conduct multi-nanosecond molecular dynamics simulations of a modeled Ku70/80 structure and several complexes with two 24-bp DNA duplexes. Free energy calculations show significant energy differences between the complexes with Ku bound at DSBs and those with Ku associated at an internal site of a chromosome. The results also reveal detailed interactions between different nucleotides and the amino acids along the DNA-binding cradle of Ku, indicating subtle binding preference of Ku at specific DNA sequences. The covariance matrix analyses along the trajectories demonstrate the protein is stimulated to undergo correlated motions of different domains once bound to DNA ends. Additionally, principle component analyses identify these low frequency collective motions suitable for binding with and translocation along duplex DNA. It is proposed that the modification of dynamical properties of Ku upon binding with DSBs may provide a signal for the further recruitment of other repair factors such as DNA-PKcs, XLF, and XRCC4.

Hu, Shaowen↗
DOE OSTI2024

Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4 CRBN , and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.

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

Metric isometries, holography, and continuous symmetry operators

In the AdS/CFT correspondence, a topological symmetry operator of the boundary conformal field theory (CFT) is dual to a dynamical brane in the gravitational bulk. Said differently, this predicts a dynamical brane for every global symmetry of the boundary CFT. We analyze this correspondence for continuous symmetries which arise from a consistent truncation of isometries on the “internal” factor 𝑋 of AdS × 𝑋. In the extra-dimensional geometry, these branes are associated with various metric singularities and do not arise from wrapped D-branes. Boosts relate configurations interpreted as topological symmetry operators and heavy defects in the CFT. From the perspective of the AdS factor, with gravity and bulk gauge fields, these are codimension-2 Gukov-Witten-like vortex configurations which are the gravity duals of 0-form symmetry operators. These effective branes come with an asymptotic tension and size which is also fully fixed by bulk dynamics. We use this higher-dimensional perspective to determine properties of the worldvolume theory for these branes. We also discuss how these considerations generalize to more general quantum field theories engineered via string theory which need not possess a semiclassical gravity dual.

anomalies↗
DOE OSTI2025

Structure-Based Design of Small-Molecule Inhibitors of Human Interleukin-6

Human Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6Rα followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. As a critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies in clinical use that either target IL-6Rα or hIL-6 to inhibit signaling. Here, we perform high-throughput structure-based computational screening using ensemble docking for small-molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein. Prior knowledge of the contact sites from binary complex studies and experimental work was incorporated into the docking studies. The top 20 scoring ligands from the in silico studies after post analysis were subjected to in vitro functional assays. Among these compounds, the ligand with the second-highest calculated binding affinity experimentally showed an ~84% inhibitory effect on IL6-induced STAT3 reporter activity at 10 μM concentration. This finding may pave the way for designing small-molecule inhibitors of hIL-6 of therapeutic significance.

Human Interleukin-6↗
DOE OSTI2025

AIMD‐Based Protocols for Modeling Exciplex Fluorescence Spectra and Inter‐System Crossing in Photocatalytic Chromophores

ABSTRACT This study introduces a computational protocol for modeling the emission spectra of exciplexes using excited‐state ab initio molecular dynamics (AIMD) simulations. The protocol is applied to a model exciplex formed by oligo‐p‐phenylenes (OPPs) and triethylamine (TEA), which is of interest in the context of photocatalytic reduction of . AIMD facilitates efficient sampling of the conformational space of OPP3 and OPP4 exciplexes with TEA, offering a dynamic alternative to previously employed static methods. The AIMD‐based protocol successfully reproduces experimental emission spectra for OPP‐TEA exciplexes, agreeing with previous computational and experimental findings. The results show that AIMD simulations provide an efficient means of sampling the conformational space of these exciplexes, requiring less user input and, in some instances, fewer computational resources than multiple excited‐state optimizations initiated from user‐specified initial structures. The study also evaluates the yield of intersystem crossing (ISC) using AIMD and Landau‐Zener probability. The results suggest that ISC is a minor decay channel for OPP3 and OPP4. This work provides new insights into the structural flexibility and emission characteristics of OPP‐TEA photoredox catalyst systems, potentially contributing to improved design strategies for organic chromophores in reduction applications.

Giudetti, Goran [Department of Chemistry Universit↗
DOE OSTI2025

Microscopic insights into the solvation of polyethylene glycol chains in water: A machine learning potential approach

Polyethylene glycol (PEG) is a structurally simple, nontoxic, and water-soluble polymer widely utilized in medical and pharmaceutical applications. Notably, when a PEG chain is immersed in water, the surrounding water molecules play a key role in driving conformational changes of this macromolecule. In this study, we explore the solvation behavior of PEG under mechanical strain using molecular dynamics simulations, with an interatomic potential obtained from machine learning. Our focus is on the transition from the favored coil-like conformation to an extended one under external force. Through analyses of radial distribution functions, hydrogen bonding, and solvation dynamics, we uncover how mechanical stretching influences the local hydration environment. Furthermore, we disentangle the enthalpic and entropic contributions to the conformational stability of PEG in water. Surprisingly, our neural network potential model identifies dewetting of PEG C-atoms, and not water H-bonding with PEG O-atoms, as the main enthalpic driving force for the coiling of PEG in water.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Uncovering Backbone Conformation for Rigid DPP-Based Donor–Acceptor Conjugated Polymer Using Deuterium Labeling and Neutron Scattering

The conjugated polymer’s backbone conformation dictates the delocalization of electrons, ultimately affecting its optoelectronic properties. Most conjugated polymers can be viewed as semirigid rods with their backbone embedded among long alkyl side chains. Thus, it is challenging to experimentally quantify the conformation of a conjugated backbone. Here, we performed contrast variation neutron scattering on rigid conjugated donor–acceptor (D–A) diketopyrrolopyrrole (DPP) polymers with selectively deuterated side chains to measure the conjugated backbone conformation. We first synthesized DPPbased polymers with deuterated side chains, confirmed by NMR and FTIR. Using contrast variation neutron scattering, we found that the DPP-based conjugated polymers are much more rigid than poly(3-alkylthiophenes), with persistence length (L p ) at 16–18 nm versus 2–3 nm. More importantly, in contrast to the relatively flexible poly(3-alkylthiophenes) whose backbone is more flexible than the whole polymer, we found that the backbone of DPP-based polymers has the same L p value compared to the whole polymer chain. This indicates that side chain interference on backbone conformation is not present for the semirigid polymer, which is further confirmed by coarse-grained molecular dynamics (CG-MD) simulations. Our work provides a novel protocol to probe polymer’s backbone conformation and paradigm-shifting understanding of the backbone conformation of semirigid conjugated polymers.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Solvent organization in the ultrahigh-resolution crystal structure of crambin at room temperature

Ultrahigh-resolution structures provide unprecedented details about protein dynamics, hydrogen bonding and solvent networks. The reported 0.70 Å, room-temperature crystal structure of crambin is the highest-resolution ambient-temperature structure of a protein achieved to date. Sufficient data were collected to enable unrestrained refinement of the protein and associated solvent networks using SHELXL . Dynamic solvent networks resulting from alternative side-chain conformations and shifts in water positions are revealed, demonstrating that polypeptide flexibility and formation of clathrate-type structures at hydrophobic surfaces are the key features endowing crambin crystals with extraordinary diffraction power.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS1978

Computer display and manipulation of biological molecules

This paper describes a computer model that was designed to investigate the conformation of molecules, macromolecules and subsequent complexes. Utilizing an advanced 3-D dynamic computer display system, the model is sufficiently versatile to accommodate a large variety of molecular input and to generate data for multiple purposes such as visual representation of conformational changes, and calculation of conformation and interaction energy. Molecules can be built on the basis of several levels of information. These include the specification of atomic coordinates and connectivities and the grouping of building blocks and duplicated substructures using symmetry rules found in crystals and polymers such as proteins and nucleic acids. Called AIMS (Ames Interactive Molecular modeling System), the model is now being used to study pre-biotic molecular evolution toward life.

Coeckelenbergh, Y.↗
DOE OSTI2024

Design of intrinsically disordered protein variants with diverse structural properties

Intrinsically disordered proteins (IDPs) perform a broad range of functions in biology, suggesting that the ability to design IDPs could help expand the repertoire of proteins with novel functions. Computational design of IDPs with specific conformational properties has, however, been difficult because of their substantial dynamics and structural complexity. We describe a general algorithm for designing IDPs with specific structural properties. We demonstrate the power of the algorithm by generating variants of naturally occurring IDPs that differ in compaction, long-range contacts, and propensity to phase separate. We experimentally tested and validated our designs and analyzed the sequence features that determine conformations. We show how our results are captured by a machine learning model, enabling us to speed up the algorithm. Our work expands the toolbox for computational protein design and will facilitate the design of proteins whose functions exploit the many properties afforded by protein disorder.

Science & Technology - Other Topics↗
DOE OSTI2025

Machine Learning‐Augmented Molecular Dynamics Simulations (MD) Reveal Insights Into the Disconnect Between Affinity and Activation of ZTP Riboswitch Ligands

Abstract The challenge of targeting RNA with small molecules necessitates a better understanding of RNA–ligand interaction mechanisms. However, the dynamic nature of nucleic acids, their ligand‐induced stabilization, and how conformational changes influence gene expression pose significant difficulties for experimental investigation. This work employs a combination of computational and experimental methods to address these challenges. By integrating structure‐informed design, crystallography, and machine learning‐augmented all‐atom molecular dynamics simulations (MD), we synthesized, biophysically and biochemically characterized, and studied the dissociation of a library of small molecule activators of the 5‐aminoimidazole–4–carboxamide ribonucleotide triphosphate (ZTP) riboswitch, a ligand‐binding RNA motif that regulates bacterial gene expression. We uncovered key interaction mechanisms, revealing valuable insights into the role of ligand binding kinetics on riboswitch activation. Further, we established that ligand on‐rates determine activation potency as opposed to binding affinity and elucidated RNA structural differences, which provide mechanistic insights into the interplay of RNA structure on riboswitch activation.

Chemistry↗
DOE OSTI2026

Free Energy and Flexibility Analysis of Autoinhibited Human BRAF

The RAF serine/threonine protein kinases function as direct effectors of RAS in the intracellular transmission of extracellular growth signals, and they are key targets for drug discovery, given the high incidence of oncogenic mutations in RAF and other components of this signaling pathway. In its inactive state, RAF is held in an autoinhibited conformation in the cytosol through a combination of intramolecular interactions and binding to a regulatory 14−3−3 protein dimer. Activation of RAF is initiated by its interaction with membrane-localized GTP-bound RAS, which induces conformational changes that release RAF from its autoinhibited state. However, the molecular mechanisms governing RAF activation remain incomplete, largely due to the challenges in experimentally capturing the intermediate conformational states in this process. To address this gap, we developed a comprehensive all-atom model of BRAF based on existing cryo-EM structures. Using this model, we performed extensive molecular dynamics simulations to evaluate the stability and free energy landscape of autoinhibited BRAF in solution. Our analysis reveals conformational flexibility within the autoinhibited complex, suggesting that this dynamic behavior may play a role in facilitating BRAF activation upon engagement with the membrane-bound RAS.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Learning Latent Representations to Bridge Coarse-Grained and Atomistic Resolutions in Polymer Simulations

We present a machine-learning-based framework for learning reduced-order representations of polymer chain conformations across coarse-grained (CG) and united-atom (UA) fidelities. By employing linear singular value decomposition and nonlinear autoencoders, we compress high-dimensional polymer configurations into latent spaces with minimal loss of structural accuracy. Crucially, we demonstrate a near-perfect linear mapping between CG and UA latent spaces, enabling an efficient super-resolution back-mapping procedure that reconstructs high-fidelity UA configurations from CG simulations. While minor structural inaccuracies occur, they are effectively corrected through a brief molecular dynamics relaxation, forming a practical hybrid machine learning−physics scheme. This approach establishes the key structural prerequisites for accelerated polymer dynamics simulations: a compact and accurate latent encoding of polymer chain conformations and a validated multi-fidelity mapping that permits reconstruction of UA structures from CG configurations. The extension of this framework to explicit time evolution within the latent space, enabling dynamics to be propagated at CG fidelity and decoded to UA resolution only when required, represents a natural and well-motivated direction for future work.

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

Depletion of the Protein Hydration Shell with Increasing Temperature Observed by Small-Angle X-ray Scattering and Molecular Simulations

The hydration shell is an integral part of proteins since it plays key roles in conformational transitions, molecular recognition, and enzymatic activity. While the dynamics of the hydration shell have been described by spectroscopic techniques, the structure of the hydration shell remains less understood due to the lack of hydration shell-sensitive structural probes with high spatial resolution. We combined temperature-ramp small-angle X-ray scattering (T-ramp SAXS) from 255 to 335 K with molecular simulations to demonstrate that the hydration shells of the IgG-binding domain of Protein G (GB3) and the villin headpiece are remarkably temperature-sensitive. For proteins in the folded state, T-ramp SAXS data and explicit-solvent SAXS predictions consistently demonstrate decays of protein contrasts and radii of gyration with increasing temperature, which are shown to reflect predominantly temperature-sensitive, depleting hydration shells. The depletion is caused not merely by enhanced disorder within the hydration shells but also by partial displacements of surface-coordinated water molecules. Together, T-ramp SAXS and explicit-solvent SAXS calculations provide a novel structural view of the protein hydration shell, which underlies temperature-dependent processes such as cold denaturation, thermophoresis, or biomolecular phase separation.

electron density↗
DOE OSTI2024

Structural characterization of ligand binding and pH-specific enzymatic activity of mouse Acidic Mammalian Chitinase

Chitin is an abundant biopolymer and pathogen-associated molecular pattern that stimulates a host innate immune response. Mammals express chitin-binding and chitin-degrading proteins to remove chitin from the body. One of these proteins, Acidic Mammalian Chitinase (AMCase), is an enzyme known for its ability to function under acidic conditions in the stomach but is also active in tissues with more neutral pHs, such as the lung. Here, we used a combination of biochemical, structural, and computational modeling approaches to examine how the mouse homolog (mAMCase) can act in both acidic and neutral environments. We measured kinetic properties of mAMCase activity across a broad pH range, quantifying its unusual dual activity optima at pH 2 and 7. We also solved high-resolution crystal structures of mAMCase in complex with oligomeric GlcNAcn, the building block of chitin, where we identified extensive conformational ligand heterogeneity. Leveraging these data, we conducted molecular dynamics simulations that suggest how a key catalytic residue could be protonated via distinct mechanisms in each of the two environmental pH ranges. These results integrate structural, biochemical, and computational approaches to deliver a more complete understanding of the catalytic mechanism governing mAMCase activity at different pH. Engineering proteins with tunable pH optima may provide new opportunities to develop improved enzyme variants, including AMCase, for therapeutic purposes in chitin degradation.

59 BASIC BIOLOGICAL SCIENCES↗