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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 307 records · Page 17
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Phosphorylation toggles the SARS-CoV-2 nucleocapsid protein between two membrane-associated condensate states

Abstract The Nucleocapsid protein (N) of SARS-CoV-2 plays a critical role in the viral lifecycle by regulating RNA replication and by packaging the viral genome. N and RNA phase separate to form condensates that may be important for these functions. Both functions occur at membrane surfaces, but how N toggles between these two membrane-associated functional states is unclear. Here, we reveal that phosphorylation switches how N condensates interact with membranes, in part by modulating condensate material properties. Our studies also show that phosphorylation alters N’s interaction with viral membrane proteins. We gain mechanistic insight through structural analysis and molecular simulations, which suggest phosphorylation induces a conformational change in N that softens condensate material properties. Together, our findings identify membrane association as a key feature of N condensates and provide mechanistic insights into the regulatory role of phosphorylation. Understanding this mechanism suggests potential therapeutic targets for COVID infection.

Science & Technology - Other Topics↗
DOE OSTI2021

Probing remdesivir nucleotide analogue insertion to SARS-CoV-2 RNA dependent RNA polymerase in viral replication

Remdesivir (RDV) prodrug can be metabolized into a triphosphate form nucleotide analogue (RDV-TP) to bind and insert into the active site of viral RNA dependent RNA polymerase (RdRp) to further interfere with viral genome replication. Here in this work, we computationally studied how RDV-TP binds and inserts to the SARS-CoV-2 RdRp active site, in comparison with natural nucleotide substrate adenosine triphosphate (ATP). To do that, we first constructed atomic structural models of an initial binding complex (active site open) and a substrate insertion complex (active site closed), based on high-resolution cryo-EM structures determined recently for SARS-CoV-2 RdRp or non-structural protein (nsp) 12, in complex with accessory protein factors nsp7 and nsp8. By conducting all-atom molecular dynamics simulation with umbrella sampling strategies on the nucleotide insertion between the open and closed state RdRp complexes, our studies show that RDV-TP can initially bind in a comparatively stabilized state to the viral RdRp active site, as it primarily forms base stacking with the template uracil nucleotide (nt +1), which under freely fluctuations supports a low free energy barrier of the RDV-TP insertion (~1.5 kcal mol -1 ). In comparison, the corresponding natural substrate ATP binds initially to the RdRp active site in Watson–Crick base pairing with the template nt, and inserts into the active site with a medium low free energy barrier (~2.6 kcal mol -1 ), when the fluctuations of the template nt are well quenched. The simulations also show that the initial base stacking of RDV-TP with the template can be specifically stabilized by motif C-S759, S682 (near motif B) with the base, and motif G-K500 with the template backbone. Although the RDV-TP insertion can be hindered by motif F-R555/R553 interaction with the triphosphate, the ATP insertion seems to be facilitated by such interactions. The inserted RDV-TP and ATP can be further distinguished by specific sugar interaction with motif B-T687 and motif A-D623, respectively.

36 MATERIALS SCIENCE↗
DOE OSTI2024

Effects of SARS-CoV-2 Main Protease Mutations at Positions L50, E166, and L167 Rendering Resistance to Covalent and Noncovalent Inhibitors

SARS-CoV-2 propagation under nirmatrelvir and ensitrelvir pressure selects for main protease (MPro) drug-resistant mutations E166V (DRM2), L50F/E166V (DRM3), E166A/L167F (DRM4), and L50F/E166A/L167F (DRM5). DRM2-DRM5 undergoes N-terminal autoprocessing to produce mature MPro with dimer dissociation constants (K dimer ) 2–3 times larger than that of the wildtype. Co-selection of L50F restores catalytic activity of DRM2 and DRM4 from ~10 to 30%, relative to that of the wild-type enzyme, without altering K dimer . Binding affinities and thermodynamic profiles that parallel the drug selection pressure, exhibiting significant decreases in affinity through entropy/enthalpy compensation, were compared with GC373. Reorganization of the active sites due to mutations observed in the inhibitor-free DRM3 and DRM4 structures as compared to MPro WT may account for the reduced binding affinities, although DRM2 and DRM3 complexes with ensitrelvir are almost identical to MPro WT -ensitrelvir. In conclusion, chemical reactivity changes of the mutant active sites due to differences in electrostatic and protein dynamics effects likely contribute to losses in binding affinities.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Optimizing Layered Control Strategies for Reducing Exposure to SARS-CoV-2

While there is growing understanding of the predominance of the airborne mode of transmission of the SARS-CoV-2 virus, there is a lack of guidance on how to build an effective system of controls to mitigate transmission in enclosed spaces. Such a system integrates multiple hazard-specific control measures to both eliminate or replace a hazard, and safeguard individuals against potential exposure and infection. Controls are defined by the US Occupational Safety and Health Association (OSHA) as the use of engineering methods to reduce the level of hazard inside a confined space. The Hierarchy of Controls provides a framework through which a system of controls can be examined; identifying those which directly remove or replace a hazard as the most effective, and individual behavioral measures (e.g., masking or shielding) as least effective. Use of such a framework to quantify control effectiveness might allow for the promotion of spaces as meeting a certain threshold of safety, likely adding to the confidence of space users resulting in increases in various metrics such as sales, visits, or likes.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2021

Low rotational barriers for the most dynamically active methyl groups in the proposed antiviral drugs for treatment of SARS-CoV-2, apilimod and tetrandrine

A recent screening study highlighted a molecular compound, apilimod, for its efficacy against the SARS-CoV-2 virus, while another compound, tetrandrine, demonstrated a remarkable synergy with the benchmark antiviral drug, remdesivir. In this work, we find that because of significantly reduced potential energy barriers, which also give rise to pronounced quantum effects, the rotational dynamics of the most dynamically active methyl groups in apilimod and tetrandrine are much faster than those in remdesivir. Because dynamics of methyl groups are essential for biochemical activity, screening studies based on the computed potential energy profiles may help identify promising candidates within a given class of drugs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Effect of Delta and Omicron Mutations on the RBD-SD1 Domain of the Spike Protein in SARS-CoV-2 and the Omicron Mutations on RBD-ACE2 Interface Complex

The receptor-binding domain (RBD) is the essential part in the Spike-protein (S-protein) of SARS-CoV-2 virus that directly binds to the human ACE2 receptor, making it a key target for many vaccines and therapies. Therefore, any mutations at this domain could affect the efficacy of these treatments as well as the viral-cell entry mechanism. We introduce ab initio DFT-based computational study that mainly focuses on two parts: (1) Mutations effects of both Delta and Omicron variants in the RBD-SD1 domain. (2) Impact of Omicron RBD mutations on the structure and properties of the RBD-ACE2 interface system. The in-depth analysis is based on the novel concept of amino acid-amino acid bond pair units (AABPU) that reveal the differences between the Delta and/or Omicron mutations and its corresponding wild-type strain in terms of the role played by non-local amino acid interactions, their 3D shapes and sizes, as well as contribution to hydrogen bonding and partial charge distributions. Our results also show that the interaction of Omicron RBD with ACE2 significantly increased its bonding between amino acids at the interface providing information on the implications of penetration of S-protein into ACE2, and thus offering a possible explanation for its high infectivity. Our findings enable us to present, in more conspicuous atomic level detail, the effect of specific mutations that may help in predicting and/or mitigating the next variant of concern.

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

Recombinant And Mix-Infection Finder for SARS-CoV-2 sample

The scientific and public health communities responded to the COVID-19 pandemic with sample acquisition and genome sequencing on a scale that eclipsed all prior sequencing efforts. While this can only be characterized as a resounding success story that has cemented the use of genomics for epidemiological investigations for any future infectious disease outbreak, several retrospective studies are cataloging an array of lessons learned and issues that have yet to be addressed in order to realize the full potential of genomics as a routine biosurveillance tool. We have been both developing methods to accurately assess SARS-CoV-2 genomes from complex samples, and analyzing the large volumes of international data, both at the consensus level and the raw sequencing data. During the course of our investigations and similar to other groups, we have examined COVID-19 samples with signatures from multiple lineages of SARS-CoV-2 and will describe some of our findings during the development of a novel workflow that incorporates detection and reporting of potential co-infection within samples and also highlights any evidence of within-host recombination.

Lo, Chien-Chi↗
DOE OSTI2022

A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection

Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents to treat diverse CoVs and as templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from a CoV disease 2019 (COVID-19) convalescent donor that exhibits broad reactivity with human β-CoVs. Here, we showed that CC40.8 targets the conserved S2 stem helix region of the CoV spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem peptide at 1.6-Å resolution and found that the peptide adopted a mainly helical structure. Conserved residues in β-CoVs interacted with CC40.8 antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibited in vivo protective efficacy against SARS-CoV-2 challenge in two animal models. In both models, CC40.8-treated animals exhibited less weight loss and reduced lung viral titers compared to controls. Furthermore, we noted that CC40.8-like bnAbs are relatively rare in human COVID-19 infection, and therefore, their elicitation may require rational structure-based vaccine design strategies. Overall, our study describes a target on β-CoV spike proteins for protective antibodies that may facilitate the development of pan–β-CoV vaccines.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations

Starting from our previous finding of 14 known drugs as inhibitors of the main protease (M pro ) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. 20 nM IC 50 values in a kinetic assay. Free-energy perturbation (FEP) calculations for M pro -ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to M pro . Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2020

Antibody dynamics to SARS‐CoV‐2 in asymptomatic COVID‐19 infections

Abstract Background The missing asymptomatic COVID‐19 infections have been overlooked because of the imperfect sensitivity of the nucleic acid testing (NAT). Globally understanding the humoral immunity in asymptomatic carriers will provide scientific knowledge for developing serological tests, improving early identification, and implementing more rational control strategies against the pandemic. Measure Utilizing both NAT and commercial kits for serum IgM and IgG antibodies, we extensively screened 11 766 epidemiologically suspected individuals on enrollment and 63 asymptomatic individuals were detected and recruited. Sixty‐three healthy individuals and 51 mild patients without any preexisting conditions were set as controls. Serum IgM and IgG profiles were further probed using a SARS‐CoV‐2 proteome microarray, and neutralizing antibody was detected by a pseudotyped virus neutralization assay system. The dynamics of antibodies were analyzed with exposure time or symptoms onset. Results A combination test of NAT and serological testing for IgM antibody discovered 55.5% of the total of 63 asymptomatic infections, which significantly raises the detection sensitivity when compared with the NAT alone (19%). Serum proteome microarray analysis demonstrated that asymptomatics mainly produced IgM and IgG antibodies against S1 and N proteins out of 20 proteins of SARS‐CoV‐2. Different from strong and persistent N‐specific antibodies, S1‐specific IgM responses, which evolved in asymptomatic individuals as early as the seventh day after exposure, peaked on days from 17 days to 25 days, and then disappeared in two months, might be used as an early diagnostic biomarker. 11.8% (6/51) mild patients and 38.1% (24/63) asymptomatic individuals did not produce neutralizing antibody. In particular, neutralizing antibody in asymptomatics gradually vanished in two months. Conclusion Our findings might have important implications for the definition of asymptomatic COVID‐19 infections, diagnosis, serological survey, public health, and immunization strategies.

Lei, Qing↗
DOE OSTI2021

Predicted success of prophylactic antiviral therapy to block or delay SARS-CoV-2 infection depends on the drug's mechanism of action

Repurposed drugs that are safe and immediately available constitute a first line of defense against new viral infections. Despite limited antiviral activity against SARS-CoV-2, several drugs are being tested as medication or as prophylaxis to prevent infection. Using a stochastic model of early phase infection, we evaluate the success of prophylactic treatment with different drug types to prevent viral infection. We find that there exists a critical efficacy that a treatment must reach in order to block viral establishment. Treatment by a combination of drugs reduces the critical efficacy, most effectively by the combination of a drug blocking viral entry into cells and a drug increasing viral clearance. Below the critical efficacy, the risk of infection can nonetheless be reduced. Drugs blocking viral entry into cells or enhancing viral clearance reduce the risk of infection more than drugs that reduce viral production in infected cells. The larger the initial inoculum of infectious virus, the less likely is prevention of an infection. In our model, we find that as long as the viral inoculum is smaller than 10 infectious virus particles, viral infection can be prevented almost certainly with drugs of 90% efficacy (or more). Even when a viral infection cannot be prevented, antivirals delay the time to detectable viral loads. The largest delay of viral infection is achieved by drugs reducing viral production in infected cells. A delay of virus infection flattens the within-host viral dynamic curve, possibly reducing transmission and symptom severity. Thus, antiviral prophylaxis, even with reduced efficacy, could be efficiently used to prevent or alleviate infection in people at high risk.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Metrics for Interzonal Dispersion Assessment of Airborne SARS-CoV-2 Within Office Buildings

High ventilation rate is increasingly considered as a mitigation strategy in the rapid spread of COVID-19 in existing buildings in addition to other options like UVGI and added filtration. However, this and other similar measures may also impact energy use and the efficiency of the buildings in which they are installed. Without concrete metrics, the impact of all these potential changes to the system cannot be properly assessed relative to the other impacts the measures might have, including additional energy use, added operation and maintenance costs, and reduced system life. Multizone airflow and contaminant transport simulations involving parameters such as infiltration rate, system configuration, and level of occupancy can provide critical information on relative risk distribution within a building. In this study, prototype airflow models are used to assess the degree to which ventilation-related measures can mitigate the spread of a virus like SARS-CoV-2 in a similar way that prototype energy models are used to study energy efficiency measures. A new detailed medium-sized office building prototype model is developed using the CONTAM software to represent contaminant transport in buildings like those modeled by the U.S. Department of Energy’s detailed medium office prototype model. The goal of this study is to generate a set of suitable metrics that will give a whole-building picture of airborne SARS-CoV-2 virus distributions across the different zones of the building under different parameters and scenarios.

DeGraw, Jason↗
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 OSTI2022

Size dependent infectivity of SARS-CoV-2 via respiratory droplets spread through central ventilation systems

In this work, we evaluate the transport of respiratory droplets that carry SARS-CoV-2 through central air handling systems in multiroom buildings. Respiratory droplet size modes arise from the bronchioles representing the lungs and lower respiratory tract, the larynx representing the upper respiratory tract including vocal cords, or the oral cavity. The size distribution of each mode remains largely conserved, although the magnitude of each droplet mode changes as infected individuals breathe, speak, sing, laugh, cough, and sneeze. Here we evaluate how each type of respiratory droplet transits through central ventilation systems and the implications thereof for infectivity of COVID-19. We find that while larger oral droplets can transmit through the air handling systems, their size and concentration are greatly reduced with but few oral droplets leaving the source room. In contrast, the smaller droplets that originate from the bronchioles and larynx are much more effective in transiting through the air handling system into connected rooms. This suggests that the ratio of lower respiratory or deep lung infections may increase relative to upper respiratory infections in rooms connected by central air handling systems. Also, increasing the temperature and humidity in the range considered after the droplets have achieved an “equilibrium” size reduces the probability of infection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Multizonal modeling of SARS-CoV-2 aerosol dispersion in a virtual office building

The dispersion of indoor airborne contaminants across different zones within a mechanically ventilated building is a complex phenomenon driven by multiple factors. In this study, we modeled the indoor dispersion of airborne SARS-CoV-2 aerosols within a US Department of Energy detailed medium office prototype building using CONTAM software. The aim of this study is to improve our understanding about how different parts of a building can experience varying concentrations of the airborne viruses under different circumstances of release and mitigation strategies. Results indicate that unventilated stairwells can have significantly higher concentrations of airborne viruses. The mitigation strategies of morning and evening flushing of conditioned zones were not found to be very effective. Instead, a constant high percentage of outdoor air in the supply mix, and the use of masks, portable HEPA air cleaners, MERV 13 or higher HVAC air filters, and ultraviolet germicidal irradiation disinfection were effective strategies to prevent airborne viral contamination in the majority of the simulated office building.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Investigation of the Effect of Temperature on the Structure of SARS-CoV-2 Spike Protein by Molecular Dynamics Simulations

Statistical and epidemiological data imply temperature sensitivity of the SARS-CoV2 coronavirus. However, the molecular level understanding of the virus structure at different temperature is still not clear. Spike protein is the outermost structural protein of the SARS-CoV-2 virus which interacts with the Angiotensin Converting Enzyme 2 (ACE2), a human receptor, and enters the respiratory system. In this study, we performed an all atom molecular dynamics simulation to study the effect of temperature on the structure of the Spike protein. After 200 ns of simulation at different temperatures, we came across some interesting phenomena exhibited by the protein. We found that the solvent exposed domain of Spike protein, namely S1, is more mobile than the transmembrane domain, S2. Structural studies implied the presence of several charged residues on the surface of N-terminal Domain of S1 which are optimally oriented at 10– 30°C. Bioinformatics analyses indicated that it is capable of binding to other human receptors and should not be disregarded. Additionally, we found that receptor binding motif (RBM), present on the receptor binding domain (RBD) of S1, begins to close around temperature of 40°C and attains a completely closed conformation at 50°C. We also found that the presence of glycan moieties did not influence the observed protein dynamics. Nevertheless, the closed conformation disables its ability to bind to ACE2, due to the burying of its receptor binding residues. Our results clearly show that there are active and inactive states of the protein at different temperatures. This would not only prove beneficial for understanding the fundamental nature of the virus, but would be also useful in the development of vaccines and therapeutics.

59 BASIC BIOLOGICAL SCIENCES↗