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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 343 records · Page 19
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Molecular Mechanisms of Nanomaterial-Bacterial Interactions Revealed by Omics—The Role of Nanomaterial Effect Level

Nanotechnology is employed across a wide range of antibacterial applications in clinical settings, food, pharmaceutical and textile industries, water treatment and consumer goods. Depending on type and concentration, engineered nanomaterials (ENMs) can also benefit bacteria in myriad contexts including within the human body, in biotechnology, environmental bioremediation, wastewater treatment, and agriculture. However, to realize the full potential of nanotechnology across broad applications, it is necessary to understand conditions and mechanisms of detrimental or beneficial effects of ENMs to bacteria. To study ENM effects, bacterial population growth or viability are commonly assessed. However, such endpoints alone may be insufficiently sensitive to fully probe ENM effects on bacterial physiology. To reveal more thoroughly how bacteria respond to ENMs, molecular-level omics methods such as transcriptomics, proteomics, and metabolomics are required. Because omics methods are increasingly utilized, a body of literature exists from which to synthesize state-of-the-art knowledge. Here we review relevant literature regarding ENM impacts on bacterial cellular pathways obtained by transcriptomic, proteomic, and metabolomic analyses across three growth and viability effect levels: inhibitory, sub-inhibitory or stimulatory. As indicated by our analysis, a wider range of pathways are affected in bacteria at sub-inhibitory vs. inhibitory ENM effect levels, underscoring the importance of ENM exposure concentration in elucidating ENM mechanisms of action and interpreting omics results. In addition, challenges and future research directions of applying omics approaches in studying bacterial-ENM interactions are discussed.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

The International Space Station Environment Triggers Molecular Responses in Aspergillus niger

Due to immense phenotypic plasticity and adaptability, Aspergillus niger is a cosmopolitan fungus that thrives in versatile environments, including the International Space Station (ISS). This is the first report of genomic, proteomic, and metabolomic alterations observed in A. niger strain JSC-093350089 grown in a controlled experiment aboard the ISS. Whole-genome sequencing (WGS) revealed that ISS conditions, including microgravity and enhanced irradiation, triggered non-synonymous point mutations in specific regions, chromosomes VIII and XII of the JSC-093350089 genome when compared to the ground-grown control. Proteome analysis showed altered abundance of proteins involved in carbohydrate metabolism, stress response, and cellular amino acid and protein catabolic processes following growth aboard the ISS. Metabolome analysis further confirmed that space conditions altered molecular suite of ISS-grown A. niger JSC-093350089. After regrowing both strains on Earth, production of antioxidant—Pyranonigrin A was significantly induced in the ISS-flown, but not the ground control strain. In summary, the microgravity and enhanced irradiation triggered unique molecular responses in the A. niger JSC-093350089 suggesting adaptive responses.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

A Novel Physiologically Based Model of Creatinine Renal Disposition to Integrate Current Knowledge of Systems Parameters and Clinical Observations

Creatinine is the most common clinical biomarker of renal function. As a substrate for renal transporters, its secretion is susceptible to inhibition by drugs, resulting in transient increase in serum creatinine and false impression of damage to kidney. Novel physiologically based models for creatinine were developed here and (dis)qualified in a stepwise manner until consistency with clinical data. Data from a matrix of studies were integrated, including systems data (common to all models), proteomics‐informed in vitro – in vivo extrapolation of all relevant transporter clearances, exogenous administration of creatinine (to estimate endogenous synthesis rate), and inhibition of different renal transporters (11 perpetrator drugs considered for qualification during creatinine model development and verification on independent data sets). The proteomics‐informed bottom‐up approach resulted in the underprediction of creatinine renal secretion. Subsequently, creatinine‐trimethoprim clinical data were used to inform key model parameters in a reverse translation manner, highlighting best practices and challenges for middle‐out optimization of mechanistic models.

Scotcher, Daniel↗
DOE OSTI2024

Chloroplast Stress Signals: Control of Retrograde Signaling, Chloroplast Turn-Over, and Cell Fate Decisions

Chloroplasts (photosynthetic plastids) are semiautonomous organelles that contain their own small genomes. The proteomes of chloroplasts, however, are a mixture of plastid and nuclear-encoded proteins. Chloroplasts perform photosynthesis, which is prone to damaging the organelles, leading to the production of reactive oxygen species (ROS) that damage the cell under environmental stresses. Thus, for the cell to maintain proper chloroplast function, efficient photosynthesis, and avoid ROS damage, it relies on complex crosstalk between the chloroplast, the nucleus, other organelles within the cell, and the cytoplasm in between. This communication involves retrograde signals from chloroplasts to control nuclear gene expression, programmed cell death (PCD), and chloroplast degradation. Here we review these signals with an emphasis on the roles of the ROS singlet oxygen ( 1 O 2 ) and plastid gene expression. We cover (1) recent work on understanding how multiple 1 O 2 signaling pathways can be initiated within stressed chloroplasts, (2) how individualized post-translational regulatory systems allow chloroplasts to control their proteomes and degradation, and (3) how chloroplast signals ultimately control cell fate decisions, such as PCD, senescence, and vacuole-mediated degradation of chloroplasts (chloroplast quality control). Overall, this chapter discusses how chloroplasts can act as environmental sensors for the cell and allow plants to acclimate to stress and thrive in dynamic environments.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Association of small vessel disease with tau pathology

Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain regions are located at the most distal areas between arterial territories, making them vulnerable to SVD-related changes. We examined the association of pathologic markers of SVD, specifically arteriolosclerosis in watershed brain regions, with AD pathologic changes. Participants (N= 982; mean age-at-death = 90; 69% women) were enrolled as part of one of two cohort studies of aging and dementia. At autopsy, neuropathological evaluation included semi-quantitative grading of arteriolosclerosis pathology from 2 cortical watershed regions: the anterior watershed (AWS) and posterior watershed (PWS), densities for cortical β-amyloid and tau-tangle pathology, and other common age-related pathologies. Linear regression models examined the association of watershed arteriolosclerosis pathology with β-amyloid and tau-tangle burden. In follow-up analyses, available ex-vivo MRI and proteomics data in a subset of decedents were leveraged to examine the association of whole brain measure of WMH, as a presumed MRI marker of SVD, with β-amyloid and tau-tangle burden, as well as to examine the association of watershed arteriolosclerosis with proteomic tau. Watershed arteriolosclerosis was common, with 45% of older persons having moderate-to-severe arteriolosclerosis pathology in the AWS region, and 35% in the PWS. In fully adjusted models that controlled for demographics and common age-related pathologies, an increase in severity of PWS arteriolosclerosis was associated with a higher burden of tau-tangle burden, specifically neocortical tau burden, but not with β-amyloid. AWS arteriolosclerosis was not associated with β-amyloid or tau pathology. Ex-vivo WMH was associated with greater tau-tangle pathology burden but not β-amyloid. Furthermore, PWS arteriolosclerosis was associated with higher abundance of tau phosphopeptides, that promote formation of tau aggregates. These data provide compelling evidence that SVD, specifically posterior watershed arteriolosclerosis pathology, is linked with tau pathological changes in the aging brain.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

The origin and evolution of viruses inferred from fold family structure

The canonical frameworks of viral evolution describe viruses as cellular predecessors, reduced forms of cells, or entities that escaped cellular control. The discovery of giant viruses has changed these standard paradigms. Their genetic, proteomic and structural complexities resemble those of cells, prompting a redefinition and reclassification of viruses. In a previous genome-wide analysis of the evolution of structural domains in proteomes, with domains defined at the fold superfamily level, we found the origins of viruses intertwined with those of ancient cells. In this review, we extend these data-driven analyses to the study of fold families confirming the co-evolution of viruses and ancient cells and the genetic ability of viruses to foster molecular innovation. The results support our suggestion that viruses arose by genomic reduction from ancient cells and validate a co-evolutionary ‘symbiogenic’ model of viral origins.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Astrocyte Reactivity by Alcohol Dependence in the Central Amygdala

Astrocytes play essential roles in the brain, but prolonged insult can result in the loss or diminishment of homeostatic functions and increased neuroinflammatory response. The central amygdala (CeA) is an important limbic region in reward and stress responsivity as well as in the development of alcohol dependence. Using a multi-omics approach with Aldh1l1-EGFP/Rpl10a mice and the chronic intermittent ethanol – two-bottle choice exposure model, we have characterized the translational response of CeA astrocytes, as well as the proteomic and phosphoproteomic changes in dependent, non-dependent, and naïve mice. We identified astrocyte-specific alterations in neuroimmune functions and antioxidant/oxidative stress pathways in dependent animals while non-dependent EtOH drinking altered cytoskeletal plasticity related pathways. Proteomic analysis showed down-regulation of astrocyte physiological functions in dependent animals while phosphoproteomic analysis identified cytoskeleton remodeling in both dependent and non-dependent animals suggesting the development of a reactive astrocyte phenotype. Astrocyte morphological reconstruction showed increased CeA astrocyte complexity in dependent and non-dependent groups compared to naïve mice. The astrocyte-specific increase in neuroimmune functions, down-regulation of astrocyte homeostatic functions, alteration in protein phosphorylation-mediated cytoskeleton remodeling, and increased astrocyte complexity demonstrate EtOH induced astrocyte activation in the CeA and suggest the presence of both adaptive and maladaptive reactive astrocytes. These findings highlight the roles CeA astrocytes play in the progression of alcohol intake to dependence and are the first step in the identification of novel astrocyte-specific therapeutic approaches for alcohol use disorder through the potentiation of adaptive changes and inhibition of maladaptive changes in astrocytes.

Hashimoto, Joel↗
DOE OSTI2026

Temporal multi-omic analysis uncovers sex-biased molecular programs underlying skeletal muscle adaptation to endurance training

Background. Exercise training is known to benefit health and reduce disease risk. While adaptations in skeletal muscles are fundamental to many of the health benefits of exercise training, the common and sex-specific molecular regulators that mediate these adaptations remain to be fully elucidated. Methods. To this end, we leveraged skeletal muscle multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), where 6 month-old male and female rats endurance trained for 1, 2, 4, or 8 weeks. Our objective was to identify shared and sex-specific multi-omic molecular responses to endurance training in skeletal muscle, and relate them to phenotypic adaptations. Results. We identified largely sexually-conserved transcriptomic and proteomic enrichments in the gastrocnemius, which correlated with skeletal muscle responses from a published exercise study in humans. We uncovered sex-consistent post-translational modifications, including decreased oxidation of MYH2 and deacetylation of the ß-oxidation enzyme HADHA. Pathway enrichment analyses revealed sex-specific remodeling across the acetylome, redox proteome, and phosphoproteome; females decreased mitochondrial protein oxidation and increased mitochondrial cristae proteins, indicative of enhanced redox buffering and mitochondrial efficiency. Despite observed decreases in the oxidation of key mitochondrial proteins, females displayed increases in the oxidation of proteins involved in glucose catabolism relative to males after 8 weeks of training, suggestive of sex-biased subcellular reactive oxygen species generation. Conclusions. This work shows a large portion of the adaptive response to endurance training in skeletal muscle is shared between females and males, while there are distinct and nuanced sex-specific adaptations that are evident, particularly at the level of post-translational regulation.

Many, Gina M.↗
DOE OSTI2023

Metatranscriptomics analysis reveals a novel transcriptional and translational landscape during Middle East respiratory syndrome coronavirus infection

Among all RNA viruses, coronavirus RNA transcription is the most complex and involves a process termed “discontinuous transcription” that results in the production of a set of 3'-nested, co-terminal genomic and subgenomic RNAs during infection. While the expression of the classic canonical set of subgenomic RNAs depends on the recognition of a 6- to 7-nt transcription regulatory core sequence (TRS), here, we use deep sequence and metagenomics analysis strategies and show that the coronavirus transcriptome is even more vast and more complex than previously appreciated and involves the production of leader-containing transcripts that have canonical and noncanonical leader-body junctions. Moreover, by ribosome protection and proteomics analyses, we show that both positive- and negative-sense transcripts are translationally active. The data support the hypothesis that the coronavirus proteome is much vaster than previously noted in the literature.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Effect of disease progression on the podocyte cell cycle in Alport Syndrome

Progression of glomerulosclerosis is associated with loss of podocytes with subsequent glomerular tuft instability. It is thought that a diminished number of podocytes may be able to preserve tuft stability through cell hypertrophy associated with cell cycle reentry. At the same time, reentry into the cell cycle risks podocyte detachment if podocytes cross the G1/S checkpoint and undergo abortive cytokinesis. In order to study cell cycle dynamics during chronic kidney disease (CKD) development, we used a FUCCI model (fluorescence ubiquitination-based cell cycle indicator) of mice with X-linked Alport Syndrome. This model exhibits progressive CKD and expresses fluorescent reporters of cell cycle stage exclusively in podocytes. With the development of CKD, an increasing fraction of podocytes in vivo were found to be in G1 or later cell cycle stages. Podocytes in G1 and G2 were hypertrophic. Heterozygous female mice, with milder manifestations of CKD, showed G1 fraction numbers intermediate between wild-type and male Alport mice. Proteomic analysis of podocytes in different cell cycle phases showed differences in cytoskeleton reorganization and metabolic processes between G0 and G1 in disease. Additionally, in vitro experiments confirmed that damaged podocytes reentered the cell cycle comparable to podocytes in vivo. Importantly, we confirmed the upregulation of PDlim2, a highly expressed protein in podocytes in G1, in a patient with Alport Syndrome, confirming our proteomics data in the human setting. Thus, our data showed that in the Alport model of progressive CKD, podocyte cell cycle distribution is altered, suggesting that cell cycle manipulation approaches may have a role in the treatment of various progressive glomerular diseases characterized by podocytopenia.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Influence of the irradiated pulmonary microenvironment on macrophage and T cell dynamics

The lung is sensitive to radiation, which increases the risk of normal tissue toxicity following radiation therapy. Adverse outcomes include pneumonitis and pulmonary fibrosis, which are thought to result from dysregulated intercellular communication within the pulmonary microenvironment. Macrophage accumulation in the lung following radiation exposure is implicated in these pathogenic outcomes. Here we investigate the role of the microenvironment in macrophage and T cell dynamics. Materials and methods C57Bl/6 mice received 6Gyx5 x-ray irradiation to the right lung. Macrophage and T cell dynamics were investigated in ipsilateral right lungs, contralateral left lungs and compared to those from non-irradiated control subjects at 4-26wk post exposure. Lungs were evaluated by flow cytometry, histology and proteomics. Results In uni-lung irradiated subjects, focal regions of macrophage accumulation were noted in both lungs by 8wk, however fibrotic lesions were observed only in ipsilateral lungs by 26wk. Both infiltrating and alveolar macrophages populations transiently expanded in both lungs, however a transitional CD11b+ alveolar macrophage population persisted only in ipsilateral lungs and expressed lower CD206. Concurrently, arginase-1+ macrophages were noted within areas of macrophage accumulation in ipsilateral but not contralateral lungs at 8 and 26wk post exposure, while CD206+ macrophages were absent from these accumulations. While CD8+ T cells were present in both lungs of irradiated subjects, T regulatory cells were only increased in ipsilateral lungs. Unbiased proteomics analysis of immune cells revealed a substantial number of differentially expressed proteins in ipsilateral lungs when compared to either contralateral or non-irradiated lungs, as well as between contralateral lungs from irradiated subjects and non-irradiated controls. Conclusions Pulmonary macrophage and T cell dynamics are impacted by the microenvironmental conditions that develop in the lung following radiation exposure, both locally and systemically. Our findings demonstrate that while macrophages and T cells infiltrate and expand in both lungs, they diverge phenotypically depending on their environment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Characterization of the procoagulant phenotype of amniotic fluid across gestation in rhesus macaques and humans

Background: Amniotic fluid (AF) plays a key role in fetal development, yet the evolving composition of AF and its effects of hemostasis and thrombosis are poorly understood. Objectives: Here, we aim to determine how the evolving molecular composition of AF relates to its procoagulant properties. Methods: We analyzed the proteomes, lipidomes and procoagulant properties of AF obtained by amniocentesis from rhesus macaque and human pregnancies at gestational-age matched timepoints. Results When added to human plasma, both rhesus and human AF accelerated clotting time and fibrin generation. We identified proteomic modules associated with clotting time and enriched for coagulation-related pathways. Proteins known to be involved in hemostasis were highly correlated with each other and their intensity of expression varied across gestation in both rhesus and humans. Inhibition of contact pathway did not affect the procoagulant effect of AF. Blocking tissue factor pathway inhibitor reversed the ability of AF to block the generation of FXa. The prothrombinase activity of AF was inhibited by phospholipid inhibitors. The levels of phosphatidylserine in AF were inversely correlated with clotting time. AF promoted platelet activation and secretion in plasma. Conclusions: The addition of AF to plasma enhances coagulation in a manner dependent on phospholipids as well as the presence of proteases and other proteins that directly regulate coagulation. We describe a correlation between clotting time and expression of coagulation proteins and phosphatidylserine in both rhesus and human AF, supporting the use rhesus models for future studies of AF biology.

amniotic fluid↗
DOE OSTI2023

Revising the dynamic energy budget theory with a new reserve mobilization rule and three example applications to bacterial growth

Dynamic energy budget (DEB) theory has been applied to model a wide range of organisms, including microbes. In the standard DEB model, biomass is partitioned into reserve and structural compartments, where reserve biomass is mobilized in a pseudolinear manner (while the reserve biomass density, defined as the ratio between reserve and structural biomass, decays linearly) to drive maintenance and the growth of structural biomass (and extracellular enzyme production if it is considered). However, the linear dynamics of the reserve biomass density makes the standard DEB model incapable of explaining the slowdown of microbial growth at high reserve density that is caused by macromolecular crowding effect which reduces biochemical reaction rates (a typical situation occurs when microbes are experiencing severe moisture stress) and is inconsistent with the observation that intracellular enzymatic reactions generally follow non-linear kinetics. By partitioning biomass into reserve, kinetic, and structural compartments, we show here that the Equilibrium Chemistry Approximation (ECA) kinetics can be used to represent enzymatically catalyzed reserve biomass mobilization that can then drive the kinetic and structural biomass synthesis. This revised DEB model better represents the tradeoff in ribosome allocation for structural growth and internal enzyme production, is structurally compatible with metabolic models of cell individuals, and includes the standard DEB model and the popular compromise model as special cases for representing population growth. We then applied the revised DEB model to interpret components of bacterial respiration, their dependence on substrate availability, and emergent microbial carbon use efficiency dynamics for an exponentially growing population. We found that the revised DEB model enables a better understanding of bacterial substrates use (carbon in our examples) than that can be derived from a few other models in the literature. In particular, the revised DEB model explains why carbon use efficiency may first increase, then plateau, and finally decrease with growth rate (and substrate uptake rate), as a function of proteomics. Additionally, the revised DEB model explains why the kinetic biomass compartment needs to be divided to reasonably incorporate proteomic control of microbial growth.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Deep learning integrates histopathology and proteogenomics at a pan-cancer level

We introduce a pioneering approach that integrates pathology imaging with transcriptomics and proteomics to identify predictive histology features associated with critical clinical outcomes in cancer. We utilize 2,755 H&E-stained histopathological slides from 657 patients across 6 cancer types from CPTAC. Our models effectively recapitulate distinctions readily made by human pathologists: tumor vs. normal (AUROC = 0.995) and tissue-of-origin (AUROC = 0.979). We further investigate predictive power on tasks not normally performed from H&E alone, including TP53 prediction and pathologic stage. Importantly, we describe predictive morphologies not previously utilized in a clinical setting. The incorporation of transcriptomics and proteomics identifies pathway-level signatures and cellular processes driving predictive histology features. Model generalizability and interpretability is confirmed using TCGA. We propose a classification system for these tasks, and suggest potential clinical applications for this integrated human and machine learning approach. A publicly available web-based platform implements these models.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Quality control of mislocalized and orphan proteins

A healthy and functional proteome is essential to cell physiology. However, this is constantly being challenged as most steps of protein metabolism are error-prone and changes in the physico-chemical environment can affect protein structure and function, thereby disrupting proteome homeostasis. Among a variety of potential mistakes, proteins can be targeted to incorrect compartments or subunits of protein complexes may fail to assemble properly with their partners, resulting in the formation of mislocalized and orphan proteins, respectively. Quality control systems are in place to handle these aberrant proteins, and to minimize their detrimental impact on cellular functions. Here, we discuss recent findings on quality control mechanisms handling mislocalized and orphan proteins. We highlight common principles involved in their recognition and summarize how accumulation of these aberrant molecules is associated with aging and disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Lipid accumulation in nitrogen and phosphorus-limited yeast is caused by less growth-related dilution

Oleaginous yeasts are used commercially to produce oleochemicals and hold potential also for biodiesel production. In response to nitrogen or phosphorous limitation, oleaginous yeasts accumulate lipids in the form of triacylglycerols. Previous work has investigated potential mechanisms by which nutrient limitation induces lipid biosynthesis without verifying whether lipid biosynthesis flux is actually enhanced. Here, in this work, we show, using 13C-glucose tracing, that in nitrogen or phosphorous limitation, lipid accumulation occurs without consistent increases in biosynthetic flux. Instead, the main driver of increased lipid pools is decreased growth-related dilution. This conclusion holds across two divergent oleaginous yeasts: Rhodotorula toruloides and Yarrowia lipolytica . Quantitative proteomics shows a substantial proteome reallocation in response to nitrogen and phosphorous limitation, with ribosomal proteins strongly downregulated, while lipid enzymes are preserved but not consistently upregulated in absolute quantity. Thus, nutrient limitation, rather than triggering greatly enhanced lipid synthesis, results in roughly sustained lipid enzyme levels and biosynthetic flux. Due to slower lipid dilution by cell division, this suffices to drive marked lipid accumulation.

09 BIOMASS FUELS↗
DOE OSTI2020

Development of Multiplexed Immuno-N-Terminomics to Reveal the Landscape of Proteolytic Processing in Early Embryogenesis of Drosophila melanogaster

Protein expression levels are regulated through both translation and degradation mechanisms. Levels of degradation intermediates, i.e., partially degraded proteins, cannot be distinguished from those of intact proteins by global proteomics analysis, which quantify total protein abundance levels. This study aimed to develop a tool for assessing the aspects of degradation regulation via proteolytic processing through a new multiplexed N-terminomics method involving selective isobaric labeling of protein N-termini and immunoaffinity capture of the labeled N-terminal peptides. Our method allows for not only identification or proteolytic cleavage sites, but also highly multiplexed quantification of proteolytic processing. In this paper, we profiled a number of potential cleavage sites by signal peptidase and provided experimental confirmation of predicted cleavage sites of signal peptide. Furthermore, the present method uniquely represents the landscape of proteomic proteolytic processing rate during early embryogenesis in Drosophila melanogaster, revealing the underlying mechanism of stringent decay regulation of zygotically expressed proteins during early stages of embryogenesis.

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

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19

In this work, we present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

60 APPLIED LIFE SCIENCES↗