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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 OSTI2024

Characterization of alternate encounter assemblies of SARS-CoV-2 main protease

The assembly of two monomeric constructs spanning segments 1-199 (MPro 1-199 ) and 10-306 (MPro 10-306 ) of SARS-CoV-2 main protease (MPro) was examined to assess the existence of a transient heterodimer intermediate in the N-terminal autoprocessing pathway of MPro model precursor. Together, they form a heterodimer population accompanied by a 13-fold increase in catalytic activity. Addition of inhibitor GC373 to the proteins increases the activity further by ~7-fold with a 1:1 complex and higher order assemblies approaching 1:2 and 2:2 molecules of MPro 1-199 and MPro 10-306 detectable by analytical ultracentrifugation and native mass estimation by light scattering. Assemblies larger than a heterodimer (1:1) are discussed in terms of alternate pathways of domain III association, either through switching the location of helix 201 to 214 onto a second helical domain of MPro 10-306 and vice versa or direct interdomain III contacts like that of the native dimer, based on known structures and AlphaFold 3 prediction, respectively. At a constant concentration of MPro 1-199 with molar excess of GC373, the rate of substrate hydrolysis displays first order dependency on the MPro 10-306 concentration and vice versa. An equimolar composition of the two proteins with excess GC373 exhibits half-maximal activity at ~6 μM MPro 1-199 . Catalytic activity arises primarily from MPro 1-199 and is dependent on the interface interactions involving the N-finger residues 1 to 9 of MPro 1-199 and E290 of MPro 10-306 . Importantly, our results confirm that a single N-finger region with its associated intersubunit contacts is sufficient to form a heterodimeric MPro intermediate with enhanced catalytic activity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Cleavage at the nsp5–nsp6 site of SARS-CoV-2 main protease intermediate precursor is faster from a monomer than a dimer form

Our previous studies of severe acute respiratory syndrome coronavirus 2 main protease (MPro) precursor monomer indicate that the initial N-terminal nonstructural protein (nsp)4/nsp5 cleavage occurs intramolecularly, with a small fraction of the active site loop equilibrium being in the active state. To understand the influence of dimer formation of MPro upon N-terminal cleavage on the subsequent C-terminal nsp5/nsp6 intermolecular cleavage kinetics, the stepwise processing of a monomeric, inactive precursor containing the native terminal cleavage sites of MPro (MBP- (−6) MPro C145A(+3) -GB1-6H, 86.2 kDa) by mature WT MPro (MPro WT ) was investigated. Differential scanning fluorimetry and analytical ultracentrifugation measurements of various MPro constructs suggest that the C145A mutation decreases the dimer dissociation constant (K dimer ) by ∼26-fold, relative to WT C145 and H41A. The monomeric precursor’s nsp4–nsp5 site appears to saturate MProWT’s active sites and cleave faster, followed by a slower first-order cleavage at the C-terminal site. No detectable product resulting from the C-terminal cleavage is observed until most of the N-terminal cleavage is complete. The initial intermediate product (termed MPro C145A-IP ) is a homodimer with an estimated K dimer of <0.05 μM. In contrast, the first-order kinetics observed for the cleavage of the monomeric form of the intermediate product is at least 300 times faster than that of the dimer form. Room-temperature X-ray structure of the MPro C145A-IP –ensitrelvir complex is like that of the MPro WT –ensitrelvir complex and reveals a dynamic C-terminal region including MPro residues 302 to 306. These results are interpreted from the point of view of a mechanism in which nsp5–nsp6 cleavage may occur from a monomeric intermediate, and dimer formation restricts this cleavage.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Visualizing the Active Site Oxyanion Loop Transition Upon Ensitrelvir Binding and Transient Dimerization of SARS-CoV-2 Main Protease

N-terminal autoprocessing from its polyprotein precursor enables creating the mature-like stable dimer interface of SARS-CoV-2 main protease (MPro), concomitant with the active site oxyanion loop equilibrium transitioning to the active conformation (E*) and onset of catalytic activity. Here, through mutagenesis of critical interface residues and evaluating noncovalent inhibitor (ensitrelvir, ESV) facilitated dimerization through its binding to MPro, we demonstrate that residues extending from Ser1 through Glu14 are critical for dimerization. Combined mutations G11A, E290A and R298A (MPro™) restrict dimerization even upon binding of ESV to monomeric MPro™ with an inhibitor dissociation constant of 7.4 ± 1.6 µM. Contrasting the covalent inhibitor NMV or GC373 binding to monomeric MPro, ESV binding enabled capturing the transition of the oxyanion loop conformations in the absence of a reactive warhead and independent of dimerization. Characterization of complexes by room-temperature X-ray crystallography reveals ESV bound to the E* state of monomeric MPro as well as an intermediate approaching the inactive state (E). It appears that the E* to E equilibrium shift occurs initially from G138-F140 residues, leading to the unwinding of the loop and formation of the 3 10 -helix. Finally, we describe a transient dimer structure of the MPro precursor held together through interactions of residues A5-G11 with distinct states of the active sites, E and E*, likely representing an intermediate in the autoprocessing pathway.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Influence of Steric and Electronic Properties of P2 Groups on Covalent Inhibitor Binding to SARS-CoV-2 Main Protease

The main protease (MPro) of SARS-CoV-2 is a critical enzyme required for viral replication, making it a prime target for antiviral drug development. Covalent inhibitors, which form a stable interaction with the catalytic C145, have demonstrated strong inhibition of MPro, but the influence of steric and electronic properties of P2 substituents, designed to engage the S2 substrate-binding subsite within the MPro active site, on inhibitor binding affinity remains underexplored. Here, in this study, we design and characterize two hybrid covalent inhibitors, BBH-3 and BBH-4, and present their X-ray crystallographic structures in complex with MPro, providing molecular insights into how their distinct P2 groups, a dichlorobenzyl moiety in BBH-3 and an adamantyl substituent in BBH-4, affect binding conformation and active site adaptability. Comparative structural analyses with previously characterized inhibitors, including BBH-2 and Mcule-5948770040, reveal how the P2 bulkiness and electronic properties influence active site dynamics, particularly through interactions with the S2 and S5 subsites. The P2 group of BBH-3 induces conformational shifts in the S2 helix and the S5 loop, while BBH-4 displaces M49, stabilizing its binding through hydrophobic interactions. Isothermal titration calorimetry further elucidates the impact of P2 modifications on inhibitor affinity, revealing a delicate balance between enthalpic and entropic contributions. The data demonstrate that BBH-3 exhibits less favorable binding, affirming that dichlorobenzyl substitution at the P2 position has a more negative impact on the affinity for MPro than bulky saturated cyclic groups. This underscores the feature that MPro active site malleability may be accompanied by a conformational strain.

SARS-CoV-2↗
DOE OSTI2022

Mechanistic investigation of SARS-CoV-2 main protease to accelerate design of covalent inhibitors

Targeted covalent inhibition represents one possible strategy to block the function of SARS-CoV-2 Main Protease (M PRO ), an enzyme that plays a critical role in the replication of the novel SARS-CoV-2. Toward the design of covalent inhibitors, we built a covalent inhibitor dataset using deep learning models followed by high throughput virtual screening of these candidates against M PRO . Two top-ranking inhibitors were selected for mechanistic investigations—one with an activated ester warhead that has a piperazine core and the other with an acrylamide warhead. Specifically, we performed a detailed analysis of the free energetics of covalent inhibition by hybrid quantum mechanics/molecular mechanics simulations. Cleavage of a fragment of the non-structured protein (NSP) from the SARS-CoV-2 genome was also simulated for reference. Simulations show that both candidates form more stable enzyme-inhibitor (E-I) complexes than the chosen NSP. It was found that both the NSP fragment and the activated ester inhibitor react with CYS145 of M PRO in a concerted manner, whereas the acrylamide inhibitor follows a stepwise mechanism. Most importantly, the reversible reaction and the subsequent hydrolysis reaction from E-I complexes are less probable when compared to the reactions with an NSP fragment, showing promise for these candidates to be the base for efficient M PRO inhibitors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Feasibility of main thermal ion heating by ICRF waves using a top launcher in a tokamak with deuterium–tritium plasmas

A scenario of ion cyclotron range of frequency (ICRF) wave injection from a top launcher is proposed as an efficient and direct heating method for thermal deuterium ions in deuterium–tritium tokamak plasmas. Positioned between the tritium cyclotron layer and ion–ion hybrid layer, the top launcher allows effective wave penetration to the ion–ion hybrid layer and enables significant power transfer to thermal deuterium. This is achieved through favorable wave polarization for fundamental cyclotron damping. There is a Doppler broadening around the cyclotron resonance and this overlaps with the ion–ion hybrid layer. Low toroidal mode numbers and ion temperature in the range of 5–20 keV are favorable for enhancing the main ion damping relative to electron damping. In contrast to the neutral beam injection, which penetration strongly depends on machine size and plasma density, the proposed ICRF-based direct ion heating scenario is shown to be scalable and applicable to both larger and smaller tokamak devices within practical constraints.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2021

Michaelis-like complex of SARS-CoV-2 main protease visualized by room-temperature X-ray crystallography

SARS-CoV-2 emerged at the end of 2019 to cause an unprecedented pandemic of the deadly respiratory disease COVID-19 that continues to date. The viral main protease (M pro ) is essential for SARS-CoV-2 replication and is therefore an important drug target. Understanding the catalytic mechanism of M pro , a cysteine protease with a catalytic site comprising the noncanonical Cys145–His41 dyad, can help in guiding drug design. Here, a 2.0 Å resolution room-temperature X-ray crystal structure is reported of a Michaelis-like complex of M pro harboring a single inactivating mutation C145A bound to the octapeptide Ac-SAVLQSGF-CONH 2 corresponding to the nsp4/nsp5 autocleavage site. The peptide substrate is unambiguously defined in subsites S5 to S3′ by strong electron density. Superposition of the Michaelis-like complex with the neutron structure of substrate-free M pro demonstrates that the catalytic site is inherently pre-organized for catalysis prior to substrate binding. Induced fit to the substrate is driven by P1 Gln binding in the predetermined subsite S1 and rearrangement of subsite S2 to accommodate P2 Leu. The Michaelis-like complex structure is ideal for in silico modeling of the SARS-CoV-2 M pro catalytic mechanism.

3CL protease↗
DOE OSTI2022

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M pro )

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M pro , is a promising target for the development of novel antiviral therapeutics. Previous X-ray crystal structures of M pro were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded M pro across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these data sets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a perturbation-dependent conformational landscape for M pro , including a mobile zinc ion interleaved between the catalytic dyad, mercurial conformational heterogeneity at various sites including a key substrate-binding loop, and a far-reaching intramolecular network bridging the active site and dimer interface. Our results may inspire new strategies for antiviral drug development to aid preparation for future coronavirus pandemics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Millinocket Stream, Maine Velocity and Bathymetry Measurements 2021

ORPC staff collected site characterization data on Millinocket Stream, downstream of the hydropower station at the former Great Northern Paper Mill site in Millinocket, Maine. Bathymetry was collected with a SonTek M9 using HydroSurveyor software package and velocity was collected using the SonTek M9 RiverSurveyor software package. Bathymetry only was collected on 9/30/21. Bathymetry and velocity were collected on 10/21/21.

16 TIDAL AND WAVE POWER↗
DOE OSTI2021

Up-Tower Investigation of Main Bearing Cage Slip and Loads

This paper described the operational conditions of an SRB in the main bearing position of a three-point mount wind turbine drivetrain. A commercial wind turbine was instrumented to measure load characteristics on the outer ring of the bearing, which were used to examine the roller load characteristics qualitatively and the cage slip quantitatively in a range of operational states. Further, a simple analytic model estimated the bearing loads and was used as input conditions to a three-dimensional finite element model. The finite element roller load results were compared to the measurements and contact stresses were also described.

17 WIND ENERGY↗
DOE OSTI2026

An Intermediate-Scale Version of the Volturnus + Floating Offshore Wind Turbine Platform Concept in a Real Ocean Environment with an Operating Turbine off the Coast of Maine (Final Scientific/Technical Report)

This project was undertaken to advance the technical readiness and commercial viability of a next-generation, industrialized concrete floating foundation for offshore wind turbines called VolturnUS +. The design objective is to deliver a platform that is lower cost, faster to manufacture, simpler to deploy, and optimized for domestic supply chains and local workforce participation. To enable project financing and commercial adoption, an at-sea demonstration under representative operating conditions was required and therefore this project aimed to deploy a ¼-scale VolturnUS+ prototype offshore the Coast of Maine.

17 WIND ENERGY↗
DOE OSTI2021

Case Study of High-Throughput Drug Screening and Remote Data Collection for SARS-CoV-2 Main Protease by Using Serial Femtosecond X-ray Crystallography

Since early 2020, COVID-19 has grown to affect the lives of billions globally. A worldwide investigation has been ongoing for characterizing the virus and also for finding an effective drug and developing vaccines. As time has been of the essence, a crucial part of this research has been drug repurposing; therefore, confirmation of in silico drug screening studies have been carried out for this purpose. Here we demonstrated the possibility of screening a variety of drugs efficiently by leveraging a high data collection rate of 120 images/second with the new low-noise, high dynamic range ePix10k2M Pixel Array Detector installed at the Macromolecular Femtosecond Crystallography (MFX) instrument at the Linac Coherent Light Source (LCLS). The X-ray Free-Electron Laser (XFEL) is used for remote high-throughput data collection for drug repurposing of the main protease (Mpro) of SARS-CoV-2 at ambient temperature with mitigated X-ray radiation damage. We obtained multiple structures soaked with nine drug candidate molecules in two crystal forms. Although our drug binding attempts failed, we successfully established a high-throughput Serial Femtosecond X-ray crystallographic (SFX) data collection protocol.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Periodic Eruptive Variability of the Isolated Pre-main-sequence Star V347 Aurigae

V347 Aurigae is associated with the small dark cloud L1438 and appears to be an isolated pre-main-sequence star located at distance d ≈ 200 pc. Multi-epoch, archival photometry reveals periodic brightness variations with amplitude V ≈ 2.0 mag occurring on timescales of ~160 days that have persisted for decades. Regular-cadence, optical imaging of the source with the Zwicky Transient Facility shows that a small reflection nebula illuminated by V347 Aur also fluctuates in brightness, at times fading completely. Multi-epoch, Keck/HIRES data suggests the presence of two distinct spectral components: a prominent emission-line-dominated spectrum with a heavily veiled continuum correlated with the bright photometric state, and an M-type absorption line spectrum associated with quiescence. All spectra exhibit strong Balmer and He i line emission, consistent with accretion, as well as high velocity emission arising from the forbidden transitions of [O i], [N ii], and [S ii] that are generally associated with collimated jets and disk winds. There is no evidence in existing high-dispersion spectroscopy or high-resolution imaging for binarity of V347 Aur. The repeating outburst events are possibly linked to accretion instabilities induced by an undetected companion or a structure within the circumstellar disk that periodically increases the mass accretion rate. V347 Aur is perhaps analogous to an EXor-type variable, though more regularly recurring.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2020

Statistics of Wide Pre-main-sequence Binaries in the Orion OB1 Association

Statistics of low-mass pre-main-sequence binaries in the Orion OB1 association with separations ranging from 0."6 to 20" (220 to 7400 au at 370 pc) are studied using images from the VISTA Orion mini survey and astrometry from Gaia. The input sample based on the CVSO catalog contains 1137 stars of K and M spectral types (masses between 0.3 and 0.9 M ⊙ ), 1021 of which are considered to be association members. There are 135 physical binary companions to these stars with mass ratios above ~0.13. The average companion fraction is 0.09 ± 0.01 over 1.2 decades in separation, slightly less than, but still consistent with, the field. We found a difference between the Ori OB1a and OB1b groups, the latter being richer in binaries by a factor of 1.6 ± 0.3. No overall dependence of the wide-binary frequency on the observed underlying stellar density is found, although in the Ori OB1a off-cloud population, these binaries seem to avoid dense clusters. The multiplicity rates in Ori OB1 and in sparse regions like Taurus differ significantly, hinting that binaries in the field may originate from a mixture of diverse populations.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2026

Technical Assistance for Mount Desert Island, Maine

Mount Desert Island, Maine, worked with researchers in the Energy Technology Innovation Partnership Project (ETIPP) to evaluate microgrid siting and sizing to assess how this technology could measurably improve critical service reliability.

24 POWER TRANSMISSION AND DISTRIBUTION↗
DOE OSTI2021

Bridging Aromatic/Antiaromatic Units: Recent Advances in Aromaticity and Antiaromaticity in Main-group and Transition-Metal Clusters from Bonding and Magnetic Analyses

Synthetic exploration and theoretical characterization of metal clusters are actively developing branches of modern inorganic chemistry. Advances in these areas constantly expand the rich structural diversity of viable species, allowing a detailed study of the fundamental characteristics of bench-stable compounds. In this minireview, we summarize recent achievements in synthesis and computational analyses of main-group and heterometallic clusters containing multiple aromatic/antiaromatic units. These systems range from bare clusters to ligand-decorated aggregates, providing a fundamental understanding of the aromaticity and antiaromaticity concepts in species exhibiting unprecedented shapes and composition. The review gives a comprehensive summary of bonding and magnetic response properties of such systems deciphered from the Adaptive Natural Density Partitioning (AdNDP) approach and induced magnetic field analyses.

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

The Bear Brook Watershed in Maine: Multi-Decadal Whole-Watershed Experimental Acidification

The Bear Brook Watershed in Maine (BBWM) is a long-term research site established to study the response of forest ecosystem function to environmental disturbances of chronic acidic deposition and ecosystem nitrogen enrichment. Starting in 1989, the West Bear (treated) watershed received bimonthly applications of ammonium sulfate [(NH4)2SO4] fertilizer from above the canopy, whereas East Bear (reference) received ambient deposition. The treatments were stopped in 2016, marking the beginning of the recovery phase. Research at the site has focused on soils, streams, and vegetation. Here, we describe data collected over three decades at the BBWM—input and stream output nutrient fluxes, quantitative soil pits and soil chemistry, and soil temperature and moisture.

Patel, Kaizad F.↗
DOE OSTI2020

Snowmelt Periods as Hot Moments for Soil N Dynamics: a Case Study in Maine, USA

We examined patterns of soil N availability during the vernal transition and how warming winter and ecosystem N status (N-enriched vs. N-limited) altered these patterns. Soils were sampled at the Bear Brook Watershed in Maine during 2015 and 2016. 2016 was a warmer winter with less snowfall than 2015, and therefore had earlier snowmelt and a longer vernal transition. Across both years, thaw periods consistently showed signs of being transition periods, especially evident in the N-enriched watershed — ammonium concentrations were highest during this period due to microbial community turnover and cell lysis, whereas nitrate concentrations were lowest due to flushing by meltwater. The N-enriched soils had 4–5-times more ammonium than the N-limited soils overall, although this difference was magnified during melt periods (10–14-fold). This indicates that the altered microbial community in the chronically N-manipulated soils might be more susceptible to community turnover and lysis during snowmelt. Our results indicate that ecosystem N status influences the response of forest soil N dynamics to a changing vernal transition in a time of accelerating climate change.

vernal transition, forest soils, nitrogen, N-enric↗