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At least 343 records · Page 19

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DOE OSTI2023

Structural characterization of an intrinsically disordered protein complex using integrated small-angle neutron scattering and computing

Characterizing structural ensembles of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins is essential for studying structure–function relationships. Due to the different neutron scattering lengths of hydrogen and deuterium, selective labeling and contrast matching in small-angle neutron scattering (SANS) becomes an effective tool to study dynamic structures of disordered systems. However, experimental timescales typically capture measurements averaged over multiple conformations, leaving complex SANS data for disentanglement. We hereby demonstrate an integrated method to elucidate the structural ensemble of a complex formed by two IDRs. We use data from both full contrast and contrast matching with residue-specific deuterium labeling SANS experiments, microsecond all-atom molecular dynamics (MD) simulations with four molecular mechanics force fields, and an autoencoder-based deep learning (DL) algorithm. From our combined approach, we show that selective deuteration provides additional information that helps characterize structural ensembles. We find that among the four force fields, a99SB-disp and CHARMM36m show the strongest agreement with SANS and NMR experiments. In addition, our DL algorithm not only complements conventional structural analysis methods but also successfully differentiates NMR and MD structures which are indistinguishable on the free energy surface. Finally, we present an ensemble that describes experimental SANS and NMR data better than MD ensembles generated by one single force field and reveal three clusters of distinct conformations. Our results demonstrate a new integrated approach for characterizing structural ensembles of IDPs.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

Effect of Solvents on Lignin–Surface Interactions via Molecular Dynamics Simulations

Lignin, an essential building block of lignocellulosic biomass, is a potential abundant source of aromatic monomers for the polymer and chemical industry. Reductive catalytic fractionation (RCF) is one promising process that can produce high yields of phenolic monomers and oligomers from lignin under different catalytic conditions. An important choice in optimizing RCF is the selection of solvent; however, detailed insights into solvent effects on lignin behaviors and interactions remain limited. Here, in this work, we perform all-atom molecular dynamics simulations to study the solvation of lignin, solvent-mediated conformational changes, and the interaction of solvated lignin oligomers with model surfaces. We focus on the behavior of an oligomeric lignin model compound in methanol, ethanol, a binary mixture of ethanol and water, and water at both the RCF reaction temperature (473 K) and room temperature. Analysis of structural features of lignin suggests that these three organic solvent systems favorably solvate lignin, resulting in a more extended conformation suitable for catalytic conversion to valuable chemicals. We further introduce model palladium (Pd) and carbon (C) surfaces to understand how solvent choice impacts adsorption onto a representative catalytic surface and support, and to quantify the competition among the reactant and solvent molecules for the surface. Unbiased simulations suggest strong adsorption of lignin on both Pd and C surfaces at 473 K, with notable solvent-mediated differences in adsorption energies. Additionally, our findings indicate that lignin adsorption is promoted by the entropy change resulting from the displacement of solvent molecules from the surface. This study provides a molecular perspective of adsorption of lignin onto varying surfaces, which is a step towards understanding and optimizing the catalytic conversion of lignin into valuable chemicals.

adsorption↗

DOE OSTI2021

Differences in the dynamics of the tandem-SH2 modules of the Syk and ZAP-70 tyrosine kinases

The catalytic activity of Syk-family tyrosine kinases is regulated by a tandem Src homology 2 module (tSH2 module). In the autoinhibited state, this module adopts a conformation that stabilizes an inactive conformation of the kinase domain. The binding of the tSH2 module to phosphorylated immunoreceptor tyrosine-based activation motifs necessitates a conformational change, thereby relieving kinase inhibition and promoting activation. We determined the crystal structure of the isolated tSH2 module of Syk and find, in contrast to ZAP-70, that its conformation more closely resembles that of the peptide-bound state, rather than the autoinhibited state. Hydrogen–deuterium exchange by mass spectrometry, as well as molecular dynamics simulations, reveal that the dynamics of the tSH2 modules of Syk and ZAP-70 differ, with most of these differences occurring in the C-terminal SH2 domain. Our data suggest that the conformational landscapes of the tSH2 modules in Syk and ZAP-70 have been tuned differently, such that the autoinhibited conformation of the Syk tSH2 module is less stable. This feature of Syk likely contributes to its ability to more readily escape autoinhibition when compared to ZAP-70, consistent with tighter control of downstream signaling pathways in T cells.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS1986

The effect of different resistivity models on magnetotail dynamics

Two-dimensional, time-dependent MHD simulations of the interaction between the solar wind and the earth's magnetosphere have been performed to study magnetotail dynamics with varying forms of anomalous resistivity. In general, the resulting models conform to the neutral line model proposed for substorms with near-earth x points and high-speed tailward flows occurring in the magnetotail. However, in the case where Joule heating is included in the physical description of the system, the near-earth x point never moves far down tail, and high-speed tailward flows never stop. Only in the case where there is no Joule heating does the x point move down tail. Simultaneously, the high-speed tailward flows cease. These results indicate that the mechanism of energy dissipation can have an important effect on reconnection processes and the global magnetospheric dynamics.

Lyon, J. G.↗

DOE OSTI2026

Tracking the protein conformational motions driving HIV-1 membrane fusion

HIV-1 Env (trimeric gp120/gp41) is the surface protein responsible for membrane fusion. The Env binds to the receptor proteins, which induces gp120 shedding leading to conformational changes of gp41 from the pre-fusion to post-fusion state, allowing its fusion peptide to embed in the host cell membrane and bringing the viral and host cell membranes together. The gp41 refolding is a target of several peptide inhibitors. Yet, the molecular mechanism of this dynamic process is still not well understood. In this study, we successfully simulate the conformational change of gp41 from pre-fusion to post-fusion state in atomistic resolution using all-atom structure-based models. We reveal that maintaining the directionality of protomer interactions in both pre-fusion and post-fusion states is crucial for gp41 refolding. Additionally, we find that HR1 inherently extends as a three-helical bundle toward the host-cell membrane without any bias. Importantly, we identify native contacts in the pre-fusion state that are critical for the proper refolding of gp41 towards the post-fusion state. Lastly, by incorporating the membrane-fusion inhibitors, T20 and SFT, we identify the most vulnerable stage in the fusion pathway that exhibits the greatest sensitivity to these drugs, which could aid in a better understanding of drug resistance mechanisms.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

STEPs-SOL, a Peptoid Force Field Parameterization to Include Solvent Effects

As peptoids (N-substituted glycines) continue to gain popularity as a class of biomimetic polymers, the importance and demand for accurate force fields in molecular simulations also grow. Building on the vacuum-optimized Systematic and Extensible Force Field for Peptoids (STEPs) force field, here we present STEPs-SOL, a novel peptoid force field parametrization that effectively incorporates solvent effects to enhance the accuracy of peptoid simulations. The development of STEPs-SOL is based on the need for precise electrostatic modeling achieved through solvent-specific partial charge optimization. Here, our systematic approach significantly improves agreement with experimental measurements, reducing the mean absolute error in cis/trans ratio predictions (ΔG c/t ) by an average of 38% across multiple peptoid residues and solvent environments. This improved parametrization addresses computational challenges associated with nonbonded energies while maintaining a workflow that relies on high-level quantum mechanical data rather than depending solely on limited experimental equilibrium properties. By evaluating the effects of conformational bias in restrained electrostatic potential (RESP) charge generation and examining their impact on peptoid conformations in various solvents, we enhance our understanding of peptoid structural dynamics while providing a more accurate modeling framework.

force field↗

DOE OSTI2022

The Unexpected Role of Cations in the Self-Assembly of Positively Charged Amphiphiles at Liquid/Liquid Interfaces

Conventional wisdom suggests that cations play a minimal role in the assembly of cationic amphiphiles. Here, we show that at liquid/liquid (L/L) interfaces, specific cation effects can modulate the assemblies of hydrophobic tails in an oil phase despite being attached to cationic headgroups in the aqueous phase. In this work, we used oligo-dimethylsiloxane (ODMS) methyl imidazolium amphiphiles to identify these specific interactions at hexadecane/aqueous interfaces. Small cations, such as Li + , bind to the O atoms in the ODMS tail and pin it to the interface, thereby imposing a kinked conformation-as evidenced by vibrational sum frequency generation spectroscopy and molecular dynamics simulations. While larger Cs + ions more readily partition to the interface, they do not form analogous complexes. Our data not only point to ways for controlling amphiphile structure at L/L interfaces but also suggest a means for the separation of Li + , or related applications, in soft-matter electronics.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2024

Stereodivergent photobiocatalytic radical cyclization through the repurposing and directed evolution of fatty acid photodecarboxylases

Despite their intriguing photophysical and photochemical activities, naturally occurring photoenzymes have not yet been repurposed for new-to-nature activities. Here we engineered fatty acid photodecarboxylases (FAPs) to catalyse unnatural photoredox radical C–C bond formation by leveraging strongly oxidizing excited-state flavoquinone cofactor. Through genome mining, rational engineering and directed evolution, we developed a panel of radical photocyclases (RAPs) to facilitate decarboxylative radical cyclisation with excellent chemo-, enantio-, and diastereoselectivities. Our high-throughput experimental workflow allowed for the directed evolution of FAPs. An orthogonal set of RAPs was engineered to access all four possible stereoisomers of stereochemical dyad, affording fully diastereo- and enantiodivergent biotransformations in asymmetric radical biocatalysis. Molecular dynamics simulations show that our evolved RAPs allow near-attack conformations to be easily accessed, enabling chemoselective radical cyclisation. The development of stereoselective RAPs provides unnatural C–C bond forming activities in natural photoenzyme families, which can be used to tame the stereochemistry of free radical-mediated reactions.

Ju, Shuyun (ORCID:000000020322104X)↗

NASA NTRS2003

Towards the Structure Determination of a Modulated Protein Crystal: The Semicrystalline State of Profilin:Actin

One of the remaining challenges to structural biology is the solution of modulated structures. While small molecule crystallographers have championed this type of structure, to date, no modulated macromolecular structures have been determined. Modulation of the molecular structures within the crystal can produce satellite reflections or a superlattice of reflections in reciprocal space. We have developed the data collection methods and strategies that are needed to collect and analyze these data. If the macromolecule's crystal lattice is composed of physiologically relevant packing contacts, structural changes induced under physiological conditions can cause distortion relevant to the function and biophysical processes of the molecule making up the crystal. By careful measurement of the distortion, and the corresponding three-dimensional structure of the distorted molecule, we will visualize the motion and mechanism of the biological macromolecule(s). We have measured the modulated diffraction pattern produced by the semicrystalline state of profilin:actin crystals using highly parallel and highly monochromatic synchrotron radiation coupled with fine phi slicing (0.001-0.010 degrees) for structure determination. These crystals present these crystals present a unique opportunity to address an important question in structural biology. The modulation is believed to be due to the formation of actin helical filaments from the actin beta ribbon upon the pH-induced dissociation of profilin. To date, the filamentous state of actin has resisted crystallization and no detailed structures are available. The semicrystalline state profilin:actin crystals provides a unique opportunity to understand the many conformational states of actin. This knowledge is essential for understanding the dynamics underlying shape changes and motility of eukaryotic cells. Many essential processes, such as cytokinesis, phagocytosis, and cellular migration depend upon the capacity of the actin microfilament system to be restructured in a controlled manner via polymerization, depolymerization, severing, cross-linking, and anchorage. The structure the semicrystalline state of profilin:actin will challenge and validate current models of muscle contraction and cell motility. The methodology and theory under development will be easily extendable to other systems.

Borgstahl, G.↗

DOE OSTI2024

Methyl α‐D‐galactopyranosyl‐(1→3)‐β‐D‐galactopyranoside and methyl β‐D‐galactopyranosyl‐(1→3)‐β‐D‐galactopyranoside: Glycosidic linkage conformation determined from MA'AT analysis

Abstract MA'ATanalysis has been applied to two biologically‐importantO‐glycosidic linkages in two disaccharides, α‐D‐Galp‐(1→3)‐β‐D‐GalpOMe (3) and β‐D‐Galp‐(1→3)‐β‐D‐GalpOMe (4). Using density functional theory (DFT) to obtain parameterized equations relating a group of trans‐O‐glycosidic NMR spin‐couplings to eitherphi(ϕ') orpsi(ψ'), and experimental 3 J COCH , 2 J COC , and 3 J COCC spin‐couplings measured in aqueous solution in 13 C‐labeled isotopomers, probability distributions ofϕ'andψ'in each linkage were determined and compared to those determined by aqueous 1‐μs molecular dynamics (MD) simulation. Good agreement was found between theMA'ATand single‐state MD conformational models of these linkages for the most part, with modest (approximately <15°) differences in the mean values ofϕ'andψ', although the envelope of allowed angles (encoded in circular standard deviations or CSDs) is consistently larger forϕ'determined fromMA'ATanalysis than from MD for both linkages. TheMA'ATmodel of the α‐Galp‐(1→3)‐β‐Galplinkage agrees well with those determined previously using conventional NMR methods ( 3 J COCH values and/or 1 H‐ 1 H NOEs), but some discrepancy was observed for the β‐Galp‐(1→3)‐β‐Galplinkage, which may arise from errors in the conventions used to describe the linkage torsion angles. Statistical analyses of X‐ray crystal structures show ranges ofϕ'andψ'for both linkages that include the mean angles determined fromMA'ATanalyses, although both angles adopt a wide range of values in the crystalline state, withϕ'in β‐Galp‐(1→3)‐β‐Galplinkages showing greater‐than‐expected conformational variability.

Chemistry↗

DOE OSTI2025

Shear-Induced Conformations of Salt-Free Polyelectrolytes in Semidilute Solutions

Here, we present coarse-grained molecular dynamics simulations of salt-free polyelectrolyte chains in semidilute solutions under simple shear flow, with full hydrodynamic interactions and explicit dipolar solvent. At equilibrium, chain orientation statistics follow a pseudo-Voigt distribution, and the structural correlation length and chain end-to-end vector autocorrelation function exhibit scaling behavior consistent with theoretical predictions for polyelectrolytes. Under shear, chains transition from coiled to stretched states and the end-to-end vector autocorrelation function reveals oscillatory dynamics at high Weissenberg numbers. Analysis of the gyration tensor and shear strain distributions identified three distinct chain populations with directional alignment along and against the shear gradient. Compared with their neutral polymer counterparts, polyelectrolytes exhibit stronger shear thinning and enhanced chain alignment under the same Weissenberg number, which is attributed to electrostatic interactions and shear-induced counterion release. These findings provide molecular insight into the distinct flow response of charged polymers and have implications for tailoring the rheological properties of polyelectrolyte-based materials.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2022

The spread of technological innovations: effects of psychology, culture and policy interventions

Technological innovations drive the evolution of human societies. The success of innovations depends not only on their actual benefits but also on how potential adopters perceive them and how their beliefs are affected by their social and cultural environment. To deepen our understanding of socio-psychological processes affecting the new technology spread, we model the joint dynamics of three interlinked processes: individual learning and mastering the new technology, changes in individual attitudes towards it, and changes in individual adoption decisions. We assume that the new technology can potentially lead to a higher benefit but achieving it requires learning. We posit that individual decision-making process as well as their attitudes are affected by cognitive dissonance and conformity with peers and an external authority. Individuals vary in different psychological characteristics and in their attitudes. We investigate both transient dynamics and long-term equilibria observed in our model. We show that early adopters are usually individuals who are characterized by low cognitive dissonance and low conformity with peers but are sensitive to the effort of an external authority promoting the innovation. We examine the effectiveness of five different intervention strategies aiming to promote the diffusion of a new technology: training individuals, providing subsidies for early adopters, increasing the visibility of peer actions, simplifying the exchange of opinions between people, and increasing the effort of an external authority. We also discuss the effects of culture on the spread of innovations. Finally, we demonstrate that neglecting the cognitive forces and the dynamic nature of individual attitudes can lead to wrong conclusions about adoption of innovations. Our results can be useful in developing more efficient policies aiming to promote the spread of new technologies in different societies, cultures and countries.

99 GENERAL AND MISCELLANEOUS↗

DOE OSTI2021

How Do Ionic Liquids “Fold” Ionenes? Computational and Experimental Analysis of Imidazolium Polymers Based on Ether and Alkyl Chain Variations Dissolved in an Ionic Liquid

Molecular dynamics (MD) simulations and complementary experiments are used here to understand the inter- and intramolecular structure and conformational properties of ionenes (i.e., cationic polymers formed from condensation reactions) dissolved in an ionic liquid (IL), 1-ethyl-3-methylimidazolium bistriflimide [C 2 mim + ][Tf 2 N - ]. The simulated structural properties are benchmarked against experimental analyses of these same polymers, mainly using dynamic light scattering (DLS) experiments. Four different imidazolium ionenes are considered, corresponding to variations in the chemistry and structure of the repeat units including: (1) poly (decylimidazolium) (PD 10 ); (2) poly (tetraethyleneglycolimidazolium) (PE 10 ); (3) alternating copolymer (P(ED) 5 ); and (4) a block copolymer (PE 5 D 5 ). Detailed computational analyses of the polymer structure and conformational properties were performed, including the radius of gyration, end-to-end distance, torsional distributions, and site-site and spatial distribution functions. Overall, there is a competition between intramolecular associations between the imidazolium groups and the ether sites in the polymers versus the intermolecular interactions of the polymer imidazolium groups with the surrounding anion molecules. The polymer with only ether linkages (PE 10 ) results in the most intramolecular interactions, leading to significant coiling behavior and chain contraction. These strong interactions reduce chain flexibility, but they also result in much more linear chain configurations and alignment of the imidazolium groups. The polymer structure is strongly affected as the concentration of alkyl groups is increased, and we find that the polymer architecture (alternating versus block copolymer) also has an important influence. Furthermore, these detailed observations are important for understanding the connection between the molecular design of imidazolium polymers and their emergent structural properties, which could lead to unique opportunities for creating polymer composites.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2021

EVAP: A two-photon imaging tool to study conformational changes in endogenous Kv2 channels in live tissues

A primary goal of molecular physiology is to understand how conformational changes of proteins affect the function of cells, tissues, and organisms. Here, we describe an imaging method for measuring the conformational changes of the voltage sensors of endogenous ion channel proteins within live tissue, without genetic modification. We synthesized GxTX-594, a variant of the peptidyl tarantula toxin guangxitoxin-1E, conjugated to a fluorophore optimal for two-photon excitation imaging through light-scattering tissue. We term this tool EVAP (Endogenous Voltage-sensor Activity Probe). GxTX-594 targets the voltage sensors of Kv2 proteins, which form potassium channels and plasma membrane–endoplasmic reticulum junctions. GxTX-594 dynamically labels Kv2 proteins on cell surfaces in response to voltage stimulation. To interpret dynamic changes in fluorescence intensity, we developed a statistical thermodynamic model that relates the conformational changes of Kv2 voltage sensors to degree of labeling. We used two-photon excitation imaging of rat brain slices to image Kv2 proteins in neurons. We found puncta of GxTX-594 on hippocampal CA1 neurons that responded to voltage stimulation and retain a voltage response roughly similar to heterologously expressed Kv2.1 protein. Our findings show that EVAP imaging methods enable the identification of conformational changes of endogenous Kv2 voltage sensors in tissue.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

How Rigid Are Anthranilamide Molecular Electrets?

As important as molecular electrets are for electronic materials and devices, conformational fluctuations strongly impact their macrodipoles and intrinsic properties. Herein, we employ molecular dynamics (MD) simulations with the polarizable charge equilibrium (PQEq) method to investigate the persistence length (L P ) of molecular electrets composed of anthranilamide (Aa) residues. The PQEq-MD dissipates the accepted static notions about Aa macromolecules, and L P represents the shortest Aa rigid segments. The classical model with a single L P value does not describe these oligomers. Introducing multiple L P values for the same macromolecule follows the observed trends and discerns the enhanced rigidity in their middle sections from the reduced stiffness at their terminal regions. Furthermore, L P distinctly depends on solvent polarity. The Aa oligomers maintain extended conformations in nonpolar solvents with L P exceeding 4 nm, while in polar media, increased conformational fluctuations reduce L P to about 2 nm. These characteristics set key guidelines about the utility of Aa conjugates for charge-transfer systems within organic electronics and energy engineering.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2021

Probing Clustering Dynamics between Silicon and PAA or LiPAA Slurries under Processing Conditions

This work explores the complex interplay between slurry aggregation, agglomeration, and conformation (i.e., shape) of poly(acrylic acid) (PAA)- and lithiated PAA-based silicon slurries as a function of the shear rate and the resulting slurry homogeneity. These values were measured by small-angle neutron scattering (SANS) and rheology-coupled ultra-SANS at conditions relevant to battery electrode casting. Different binder solution preparation methods, either a ball milling (BM) process or a planetary centrifugal mixing (PCM) process, dramatically modify the resulting polymer dynamics and organization around a silicon material. This is due to the different energy profiles of mixing where the more violent and higher energy PCM causes extensive breakdown and reformation of the binder, which is now likely in a branched conformation, while the lower energy BM results in simply lower-molecular weight linear polymers. In conclusion, the breakdown and reorganization of the polymer structure affect silicon slurry homogeneity, which affects subsequent electrode architecture.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2020

X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release

Neurotransmitter:sodium symporters (NSS) are conserved from bacteria to man and serve as targets for drugs, including antidepressants and psychostimulants. Here we report the X-ray structure of the prokaryotic NSS member, LeuT, in a Na+/substrate-bound, inward-facing occluded conformation. To obtain this structure, we were guided by findings from single-molecule fluorescence spectroscopy and molecular dynamics simulations indicating that L-Phe binding and mutation of the conserved N-terminal Trp8 to Ala both promote an inward-facing state. Compared to the outward-facing occluded conformation, our structure reveals a major tilting of the cytoplasmic end of transmembrane segment (TM) 5, which, together with release of the N-terminus but without coupled movement of TM1, opens a wide cavity towards the second Na + binding site. The structure of this key intermediate in the LeuT transport cycle, in the context of other NSS structures, leads to the proposal of an intracellular release mechanism of substrate and ions in NSS proteins.

Science & Technology - Other Topics↗

DOE OSTI2024

Changes in an enzyme ensemble during catalysis observed by high-resolution XFEL crystallography

Enzymes populate ensembles of structures necessary for catalysis that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography at an x-ray free electron laser to observe catalysis in a designed mutant isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations, and formation of the thioimidate intermediate selects for catalytically competent substates. The influence of cysteine ionization on the ICH ensemble is validated by determining structures of the enzyme at multiple pH values. Large molecular dynamics simulations in crystallo and time-resolved electron density maps show that Asp 17 ionizes during catalysis and causes conformational changes that propagate across the dimer, permitting water to enter the active site for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.

59 BASIC BIOLOGICAL SCIENCES↗