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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 163 records · Page 9
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

On the advantages of exploiting memory in Markov state models for biomolecular dynamics

Biomolecular dynamics play an important role in numerous biological processes. Markov State Models (MSMs) provide a powerful approach to study these dynamic processes by predicting long time scale dynamics based on many short molecular dynamics (MD) simulations. In an MSM, protein dynamics are modeled as a kinetic process consisting of a series of Markovian transitions between different conformational states at discrete time intervals (called “lag time”). To achieve this, a master equation must be constructed with a sufficiently long lag time to allow interstate transitions to become truly Markovian. This imposes a major challenge for MSM studies of proteins since the lag time is bound by the length of relatively short MD simulations available to estimate the frequency of transitions. Here, we show how one can employ the generalized master equation formalism to obtain an exact description of protein conformational dynamics both at short and long time scales without the time resolution restrictions imposed by the MSM lag time. Using a simple kinetic model, alanine dipeptide, and WW domain, we demonstrate that it is possible to construct these quasi-Markov State Models (qMSMs) using MD simulations that are 5–10 times shorter than those required by MSMs. These qMSMs only contain a handful of metastable states and, thus, can greatly facilitate the interpretation of mechanisms associated with protein dynamics. A qMSM opens the door to the study of conformational changes of complex biomolecules where a Markovian model with a few states is often difficult to construct due to the limited length of available MD simulations.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

A mini-TGA protein modulates gene expression through heterogeneous association with transcription factors

Abstract TGA (TGACG-binding) transcription factors, which bind their target DNA through a conserved basic region leucine zipper (bZIP) domain, are vital regulators of gene expression in salicylic acid (SA)-mediated plant immunity. Here, we investigated the role of StTGA2.1, a potato (Solanum tuberosum) TGA lacking the full bZIP, which we named a mini-TGA. Such truncated proteins have been widely assigned as loss-of-function mutants. We, however, confirmed that StTGA2.1 overexpression compensates for SA-deficiency, indicating a distinct mechanism of action compared with model plant species. To understand the underlying mechanisms, we showed that StTGA2.1 can physically interact with StTGA2.2 and StTGA2.3, while its interaction with DNA was not detected. We investigated the changes in transcriptional regulation due to StTGA2.1 overexpression, identifying direct and indirect target genes. Using in planta transactivation assays, we confirmed that StTGA2.1 interacts with StTGA2.3 to activate StPRX07, a member of class III peroxidases (StPRX), which are known to play role in immune response. Finally, via structural modeling and molecular dynamics simulations, we hypothesized that the compact molecular architecture of StTGA2.1 distorts DNA conformation upon heterodimer binding to enable transcriptional activation. This study demonstrates how protein truncation can lead to distinct functions and that such events should be studied carefully in other protein families.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

The structural plasticity of nucleic acid duplexes revealed by WAXS and MD

Double-stranded DNA (dsDNA) and RNA (dsRNA) helices display an unusual structural diversity. Some structural variations are linked to sequence and may serve as signaling units for protein-binding partners. Therefore, elucidating the mechanisms and factors that modulate these variations is of fundamental importance. While the structural diversity of dsDNA has been extensively studied, similar studies have not been performed for dsRNA. Because of the increasing awareness of RNA’s diverse biological roles, such studies are timely and increasingly important. We integrate solution x-ray scattering at wide angles (WAXS) with all-atom molecular dynamics simulations to explore the conformational ensemble of duplex topologies for different sequences and salt conditions. These tightly coordinated studies identify robust correlations between features in the WAXS profiles and duplex geometry and enable atomic-level insights into the structural diversity of DNA and RNA duplexes. Notably, dsRNA displays a marked sensitivity to the valence and identity of its associated cations.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2024

Engineered living materials for capture, conversion, and recycling technologies

Continued dependence on crude oil and natural gas resources for fossil fuels has caused global atmospheric carbon dioxide (CO 2 ) emissions to increase to record-setting proportions. There is an urgent need for efficient and inexpensive carbon sequestration systems to mitigate large-scale CO 2 emissions from industrial flue gas. Carbonic anhydrase (CA) has shown high potential for enhanced CO 2 capture applications compared to conventional absorption-based methods currently utilized in various industrial settings. This study aims to understand structural aspects that contribute to the stability of CA enzymes critical for their applications in industrial processes, which require the ability to withstand conditions different from their native environments. Here, we evaluated the thermostability and enzyme activity of mesophilic and thermophilic CA variants at different temperature conditions and in the presence of atmospheric gas pollutants like nitrogen oxides (NO x ) and sulphur oxides (SO x ). Based on our enzyme activity assays and molecular dynamics simulations, we see increased conformational stability and CA activity levels in thermostable CA variants incubated week-long at different temperature conditions. The thermostable CA variants also retained high levels of CA activity despite changes in solution pH due to increasing NO x and SO x concentrations. Furthermore, a loss of CA activity was observed only at high concentrations of NO x /SO x that possibly can be minimized with appropriate buffered solutions.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Using Metadynamics to Reveal Extractant Conformational Free Energy Landscapes

Understanding the impact of extractant functionalization on metal-binding energetics in liquid-liquid extraction is essential to guide the development of better separation processes. Traditionally, computational extractant design uses electronic structure calculations on metal-ligand clusters to determine the metal-binding energy of the lowest energy state. Although highly accurate, this approach does not account for all of the relevant physics encountered under experimental conditions. Such methodologies often neglect entropic contributions such as temperature effects and ligand flexibility, in addition to approximating solvent-extractant interactions with implicit solvent models. In this study, we use classical molecular dynamics simulations with an advanced sampling method, metadynamics, to map out extractant molecule conformational free energies in the condensed phase. Here we generate the complete conformational landscape in solution for a family of bidentate malonamide-based extractants with different functionalizations of the headgroup and the side chains. In particular, we show how such alkyl functionalization reshapes the free energy landscape, affecting the free energy penalty of organizing the extractant into the cis-like metal-binding conformation from the trans-like conformation of the free extractant in solution. Specifically, functionalizing alkyl tails to the center of the headgroup has a greater influence on increasing molecular rigidity and disfavoring the binding conformation than functionalizing side chains. These findings are consistent with trends in metal-binding energetics based on experimentally reported distribution ratios. We also consider a different bidentate extractant molecule, carbamoylmethylphosphine oxide, and show how the choice of solvent can further reshape the conformational energetic landscape. This study demonstrates the feasibility of using molecular dynamics simulations with advanced sampling techniques to investigate extractant conformational energetics in solution, which, more broadly, will enable extractant design that accounts for entropic effects and explicit solvation.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Visualizing group II intron dynamics between the first and second steps of splicing

Group II introns are ubiquitous self-splicing ribozymes and retrotransposable elements evolutionarily and chemically related to the eukaryotic spliceosome, with potential applications as gene-editing tools. Recent biochemical and structural data have captured the intron in multiple conformations at different stages of catalysis. Here, we employ enzymatic assays, X-ray crystallography, and molecular simulations to resolve the spatiotemporal location and function of conformational changes occurring between the first and the second step of splicing. We show that the first residue of the highly-conserved catalytic triad is protonated upon 5’-splice-site scission, promoting a reversible structural rearrangement of the active site (toggling). Protonation and active site dynamics induced by the first step of splicing facilitate the progression to the second step. Our insights into the mechanism of group II intron splicing parallels functional data on the spliceosome, thus reinforcing the notion that these evolutionarily-related molecular machines share the same enzymatic strategy.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Correlated Response of Protein Side-Chain Fluctuations and Conformational Entropy to Ligand Binding

The heterogeneous fast side-chain dynamics of proteins plays crucial roles in molecular recognition and binding. Site-specific NMR experiments quantify these motions by measuring the model-free order parameter (O axis 2 ) on a scale of 0 (most flexible) to 1 (least flexible) for each methyl-containing residue of proteins. In this work, we have examined ligand-induced variations in the fast side-chain dynamics and conformational entropy of calmodulin (CaM) using five different CaM–peptide complexes. O axis 2 of CaM in the ligand-free (O axis,U 2 ) and ligand-bound (O axis,B 2 ) states are calculated from molecular dynamics trajectories and conformational energy surfaces obtained using the adaptive biasing force (ABF) method. ΔO axis 2 = O axis,B 2 – O axis,U 2 follows a Gaussian-like unimodal distribution whose second moment is a potential indicator of the binding affinity of these complexes. The probability for the binding-induced O axis,U 2 → O axis,B 2 transition decreases with increasing magnitude of ΔO axis 2 , indicating that large flexibility changes are improbable for side chains of CaM after ligand binding. A linear correlation established between ΔOaxis2 and the conformational entropy change of the protein makes possible the determination of the conformational entropy of binding of protein–ligand complexes. The results not only underscore the functional importance of fast side-chain fluctuations but also highlight key motional and thermodynamic correlates of protein–ligand binding.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Chain and Segmental Dynamics in Polymer–Nanoparticle Composites with High Nanoparticle Loading

Recent experimental and simulation studies have shown that polymer–nanoparticle (NP) composites (PNCs) with ultra-high NP loading (>50%) exhibit remarkable mechanical properties and dramatic increases in polymer glass-transition temperature, viscosity, and thermal stability compared to the bulk polymer. These deviations in macroscopic properties suggest a slowdown in both segmental and chain-scale polymer dynamics due to confinement. In this work, we examine the polymer conformations and dynamics in these PNCs using molecular dynamics simulations of both unentangled and entangled coarse-grained polymers in random-close-packed NP packings with varying polymer fill fractions. We find that the changes in the polymer dynamics depend on the number of NPs in contact with a polymer segment. Using the number of polymer–NP contacts and different polymer chain conformations as criteria for categorization, we further examine the polymer dynamics at multiple length scales to show the high level of dynamic heterogeneity in PNCs with ultra-high NP loading.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Paired Simulations and Experimental Investigations into the Calcium-Dependent Conformation of Albumin

Serum albumin is the most abundant protein in blood plasma, and it is involved in multiple biological processes. Serum albumin has recently been adapted for improving biomaterial integration with bone tissue, and studies have shown the importance of this protein in bone repair and regeneration. However, the mechanism of action is not yet clear. In stark contrast, other studies have demonstrated that albumin blocks cell adhesion to surfaces, which is seen as a limitation to its bone healing role. These apparent contradictions suggest that the conformation of albumin facilitates its bioactivity, leading to enhanced bone repair. Serum albumin is known to play a major role in maintaining the calcium ion concentration in blood plasma. Due to the prevalence of calcium at bone repair and regeneration sites, it has been hypothesized that calcium binding to serum albumin triggers a conformational change, leading to bioactivity. In the current study, molecular modeling approaches including molecular docking, atomic molecular dynamics (MD) simulation, and coarse-grained MD simulation were used to test this hypothesis by investigating the conformational changes induced in bovine serum albumin by interaction with calcium ions. The computational results were qualitatively validated with experimental Fourier-transform infrared spectroscopy analysis. We find that free calcium ions in solution transiently bind with the three major loops in albumin, triggering a conformational change where N-terminal and C-terminal domains separate from each other in a partial unfolding process. The separation distance between these domains was found to correlate with the calcium ion concentration. The experimental data support the simulation results showing that albumin has enhanced conformational heterogeneity upon exposure to intermediate levels of calcium, without any significant secondary structure changes.

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

Dynamics of fluorinated imide-based ionic liquids using nuclear magnetic resonance techniques

There is increasing interest in studying molecular motions in ionic liquids to gain better insights into their transport properties and to expand their applications. Here, in this study, we have employed the fast field cycling relaxometry and pulsed field gradient nuclear magnetic resonance techniques to investigate the rotational and translational dynamics of fluorinated imide-based ionic liquids (ILs) at different temperatures. We have studied a total of six ILs composed of the 1-butyl-3-methylimidazolium cation ([BMIM] + ) combined with chemically modified analogs of the bis((trifluoromethyl)sulfonyl)imide anion ([NTf 2 ] − or [TFSI] − ). The primary objective of this paper is to broaden the understanding of how the anion's conformational flexibility, fluorination, and mass affect the molecular dynamics of cations and anions. Our results indicate that flexibility has the most significant impact on the rotational and translational motions of ions. Meanwhile, the effect of fluorination and mass is only relevant when conformational flexibility does not change significantly between the ILs being compared.

25 ENERGY STORAGE↗
DOE OSTI2022

Different Enzyme Conformations Induce Different Mechanistic Traits in HIV‐1 Protease

Abstract The influence of the dynamical flexibility of enzymes on reaction mechanisms is a cornerstone in biological sciences. In this study, we aim to 1) study the convergence of the activation free energy by using the first step of the reaction catalysed by HIV‐1 protease as a case study, and 2) provide further evidence for a mechanistic divergence in this enzyme, as two different reaction pathways were seen to contribute to this step. We used quantum mechanics/molecular mechanics molecular dynamics simulations, on four different initial conformations that led to different barriers in a previous study. Despite the sampling, the four activation free energies still spanned a range of 5.0 kcal ⋅ mol −1 . Furthermore, the new simulations did confirm the occurrence of an unusual mechanistic divergence, with two different mechanistic pathways displaying equivalent barriers. An active‐site water molecule is proposed to influence the mechanistic pathway.

Coimbra, João T. S.↗
DOE OSTI2024

Multiscale Modeling of Vinyl-Addition Polynorbornenes: The Effect of Stereochemistry

Vinyl-addition polynorbornenes are candidates for designing high-performance polymers due to unique characteristics, which include a high glass transition temperature associated with a rigid backbone. Recent studies have established that the processability and properties of these polymers can be fine-tuned by using targeted substitutions. However, synthesis with different catalysts results in materials with distinct properties, potentially due to the presence of various stereoisomers that are difficult to quantify experimentally. Herein, we develop all-atom models of polynorbornene oligomers based on classical force fields and density functional theory. To establish the relationship between chemical architecture, chain conformations, and melt structure, we perform detailed molecular dynamics simulations with the fine-tuned atomistic force field and propose simpler coarse-grained descriptions to address the high molecular weight limit. All-atom simulations of oligomers suggest high glass transition temperatures in the range of 550–600 K. In the melt state (800 K), meso chains form highly rigid extended coils (C∞≈11) with amorphous structural characteristics similar to the X-ray diffraction data observed in the literature. In contrast, simulations with racemo chains predict highly helical tubular chain conformations that could promote assembly into crystalline structures.

Polymer Science↗
DOE OSTI2025

Conformational heterogeneity in the dGsw purine riboswitch: role of Mg²⁺ and 2’-dG in aptamer folding

Recent advancements in RNA structural biology have focused on unraveling the complexities of non-coding mRNA elements like riboswitches. These cis-acting regulatory regions undergo structural changes in response to specific cellular metabolites, leading to up or downregulation of downstream genes. The purine riboswitch family regulates many prokaryotic genes involved in purine degradation and biosynthesis. They feature an aptamer domain organized around a 3-way helical junction, where ligand encapsulation occurs at the junctional core. In our study, we chemically probed the aptamer domain of the 2’-dG-sensing purine riboswitch from Mesoplasma florum (dGsw) under various solution conditions to understand how Mg²⁺ and 2’-dG influence riboswitch folding. Here, we find that efficient 2’-dG binding strongly depends on Mg²⁺, indicating that Mg²⁺ is essential for priming dGsw for ligand interactions. We identified a previously undescribed sequence in the 5’ tail of dGsw that is complementary to a conserved helix. The inclusion of this region in a construct led to intramolecular competition between the alternate helix, Palt, and P1. Mutational analysis confirmed that 5’ flanking end of the aptamer domain forms an alternate helix in the absence of ligand. Molecular dynamics simulations revealed that this alternative conformation is stable. This helix may, therefore, facilitate the formation of an anti-terminator helix by opening the 3-way junction surrounding the 2’-dG binding site. Our study further establishes the importance of a closed terminal P1 helix conformation for metabolite binding and suggests that the delicate interplay between P1 and Palt may fine-tune downstream gene regulation. These insights offer a new perspective on riboswitch structure and enhance our understanding of the role that a conformational ensemble plays in riboswitch activity and regulation.

Biochemistry & Molecular Biology↗
DOE OSTI2023

Atomistic Simulations of Polydisperse Lignin Melts Using Simple Polydisperse Residue Input Generator

Understanding the physics of lignin will help rationalize its function in plant cell walls as well as aiding practical applications such as deriving biofuels and bioproducts. Here, in this work, we present SPRIG (Simple Polydisperse Residue Input Generator), a program for generating atomic-detail models of random polydisperse lignin copolymer melts i.e., the state most commonly found in nature. Using these models, we use all-atom molecular dynamics (MD) simulations to investigate the conformational and dynamic properties of polydisperse melts representative of switchgrass (Panicum virgatum L.) lignin. Polydispersity, branching and monolignol sequence are found to not affect the calculated glass transition temperature, T g . The Flory–Huggins scaling parameter for the segmental radius of gyration is 0.42 ± 0.02, indicating that the chains exhibit statistics that lie between a globular chain and an ideal Gaussian chain. Below T g the atomic mean squared displacements are independent of molecular weight. In contrast, above T g , they decrease with increasing molecular weight. Therefore, a monodisperse lignin melt is a good approximation to this polydisperse lignin when only static properties are probed, whereas the molecular weight distribution needs to be considered while analyzing lignin dynamics.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Conformation and dynamics of ring polymers under symmetric thin film confinement

Understanding the structure and dynamics of polymers under confinement has been of widespread interest, and one class of polymers that have received comparatively little attention under confinement is that of ring polymers. The properties of non-concatenated ring polymers can also be important in biological fields because ring polymers have been proven to be a good model to study DNA organization in the cell nucleus. From our previous study, linear polymers in a cylindrically confined polymer melt were found to segregate from each other as a result of the strong correlation hole effect that is enhanced by the confining surfaces. By comparison, our subsequent study of linear polymers in confined thin films at similar levels of confinements found only the onset of segregation. Here, we use molecular dynamics simulation to investigate the chain conformations and dynamics of ring polymers under planar (1D) confinement as a function of film thickness. Our results show that conformations of ring polymers are similar to the linear polymers under planar confinement, except that ring polymers are less compressed in the direction normal to the walls. While we find that the correlation hole effect is enhanced under confinement, it is not as pronounced as the linear polymers under 2D confinement. Finally, we show that chain dynamics far above Tg are primarily affected by the friction from walls based on the monomeric friction coefficient we get from the Rouse mode analysis.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Dynamics of Cation-Induced Conformational Changes in Nanometer-Sized Uranyl Peroxide Clusters

Conformational changes of the pyrophosphate (Pp)-functionalized uranyl peroxide nanocluster [(UO 2 ) 24 (O 2 ) 24 (P 2 O 7 ) 12 ] 48– ({U 24 Pp 12 }), dissolved as a Li/Na salt, can be induced by the titration of alkali cations into solution. The most symmetric conformer of the molecule has idealized octahedral ( O h ) molecular symmetry. One-dimensional 31 P NMR experiments provide direct evidence that both K + and Rb + ions trigger an O h -to- D 4 h conformational change within {U 24 Pp 12 }. Variable-temperature 31 P NMR experiments conducted on partially titrated {U 24 Pp 12 } systems show an effect on the rates; increased activation enthalpy and entropy for the D 4 h -to- O h transition is observed in the presence of Rb + compared to K + . Two-dimensional, exchange spectroscopy 31 P NMR revealed that magnetization transfer links chemically unique Pp bridges that are present in the D 4 h conformation and that this magnetization transfer occurs via a conformational rearrangement mechanism as the bridges interconvert between two symmetries. The interconversion is triggered by the departure and reentry of K (or Rb) cations out of and into the cavity of the cluster. This rearrangement allows Pp bridges to interconvert without the need to break bonds. Cs ions exhibit unique interactions with {U 24 Pp 12 } clusters and cause only minor changes in the solution 31 P NMR signatures, suggesting that O h symmetry is conserved. Single-crystal X-ray diffraction measurements reveal that the mixed Li/Na/Cs salt adopts D 2 h molecular symmetry, implying that while solvated, this cluster is in equilibrium with a more symmetric form. Thus, these results highlight the unusually flexible nature of the actinide-based {U 24 Pp 12 } and its sensitivity to countercations in solution.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

High-Performance Non-fullerene organic solar cells enabled by noncovalent Conformational locks and Side-Chain engineering

Three novel small molecular acceptors (SMAs) BO-2F, BO-C8-2F and BO-C2C6-C8-2F were designed and synthesized. These acceptors all possess planar molecular backbone because of the introduction of intramolecular noncovalent interaction. Among them, BO-C2C6-C8-2F with four side chains, which has the highest solubility, can form more appropriate nanomorphology when blending with PBDB-T. Hence, organic solar cells (OSCs) based on PBDB-T:BO-C2C6-C8-2F displayed an outstanding power convesion efficiency (PCE) of 14.25%, which is higher than BO-2F and BO-C8-2F based ones. To the best of our knowledge, the PCE of 14.25% is one of the highest for the OSCs based on A-π-D-π-A type SMAs. Finally, our results have demonstrated that the combination of side-chain engineering and intramolecular conformation lock has a great prospect in the design of high performance SMAs for OSCs.

14 SOLAR ENERGY↗
DOE OSTI2022

Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry

Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated in diseases. A key step in this process is the formation of a ternary complex where a heterobifunctional molecule induces proximity of an E3 ligase to a protein of interest (POI), thus facilitating ubiquitin transfer to the POI. In this work, we characterize 3 steps in the TPD process. (1) We simulate the ternary complex formation of SMARCA2 bromodomain and VHL E3 ligase by combining hydrogen-deuterium exchange mass spectrometry with weighted ensemble molecular dynamics (MD). (2) We characterize the conformational heterogeneity of the ternary complex using Hamiltonian replica exchange simulations and small-angle X-ray scattering. (3) We assess the ubiquitination of the POI in the context of the full Cullin-RING Ligase, confirming experimental ubiquitinomics results. Differences in degradation efficiency can be explained by the proximity of lysine residues on the POI relative to ubiquitin.

59 BASIC BIOLOGICAL SCIENCES↗