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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 1,009 records · Page 56
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Metagenome-assembled genomes provide insight into the metabolic potential during early production of Hydraulic Fracturing Test Site 2 in the Delaware Basin

Demand for natural gas continues to climb in the United States, having reached a record monthly high of 104.9 billion cubic feet per day (Bcf/d) in November 2023. Hydraulic fracturing, a technique used to extract natural gas and oil from deep underground reservoirs, involves injecting large volumes of fluid, proppant, and chemical additives into shale units. This is followed by a “shut-in” period, during which the fracture fluid remains pressurized in the well for several weeks. The microbial processes that occur within the reservoir during this shut-in period are not well understood; yet, these reactions may significantly impact the structural integrity and overall recovery of oil and gas from the well. To shed light on this critical phase, we conducted an analysis of both pre-shut-in material alongside production fluid collected throughout the initial production phase at the Hydraulic Fracturing Test Site 2 (HFTS 2) located in the prolific Wolfcamp formation within the Permian Delaware Basin of west Texas, USA. Specifically, we aimed to assess the microbial ecology and functional potential of the microbial community during this crucial time frame. Prior analysis of 16S rRNA sequencing data through the first 35 days of production revealed a strong selection for a Clostridia species corresponding to a significant decrease in microbial diversity. Here, we performed a metagenomic analysis of produced water sampled on Day 33 of production. This analysis yielded three high-quality metagenome-assembled genomes (MAGs), one of which was a Clostridia draft genome closely related to the recently classified Petromonas tenebris. This draft genome likely represents the dominant Clostridia species observed in our 16S rRNA profile. Annotation of the MAGs revealed the presence of genes involved in critical metabolic processes, including thiosulfate reduction, mixed acid fermentation, and biofilm formation. These findings suggest that this microbial community has the potential to contribute to well souring, biocorrosion, and biofouling within the reservoir. Our research provides unique insights into the early stages of production in one of the most prolific unconventional plays in the United States, with important implications for well management and energy recovery.

natural gas↗
DOE OSTI2013

The physiological resilience of fern sporophytes and gametophytes: advances in water relations offer new insights into an old lineage

Ferns are some of the oldest vascular plants in existence and they are the second most diverse lineage of tracheophytes next to angiosperms. Recent efforts to understand fern success have focused on the physiological capacity and stress tolerance of both the sporophyte and the gametophyte generations. In this review, we examine these insights through the lens of plant water relations, focusing primarily on the form and function of xylem tissue in the sporophyte, as well as the tolerance to and recovery from drought and desiccation stress in both stages of the fern life cycle. The absence of secondary xylem in ferns is compensated by selection for efficient primary xylem composed of large, closely arranged tracheids with permeable pit membranes. Protection from drought-induced hydraulic failure appears to arise from a combination of pit membrane traits and the arrangement of vascular bundles. Features such as tracheid-based xylem and variously sized megaphylls are shared between ferns and more derived lineages, and offer an opportunity to compare convergent and divergent hydraulic strategies critical to the success of xylem-bearing plants. Fern gametophytes show a high degree of desiccation tolerance but new evidence shows that morphological attributes in the gametophytes may facilitate water retention, though little work has addressed the ecological significance of this variation. We conclude with an emergent hypothesis that selection acted on the physiology of both the sporophyte and gametophyte generations in a synchronous manner that is consistent with selection for drought tolerance in the epiphytic niche, and the increasingly diverse habitats of the mid to late Cenozoic.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2019

Comparative Genomics Analysis Provides New Insight Into Molecular Basis of Stomatal Movement in Kalanchoë fedtschenkoi

CO 2 uptake and water loss in plants are regulated by microscopic pores on the surface of leaves, called stomata. This enablement of gas exchange by the opening and closing of stomata is one of the most essential processes in plant photosynthesis and transpiration, affecting water-use efficiency (WUE) and thus drought susceptibility. In plant species with crassulacean acid metabolism (CAM) photosynthesis, diel stomatal movement pattern is inverted relative to C 3 and C 4 photosynthesis species, resulting in much higher WUE and drought tolerance. However, little is known about the molecular basis of stomatal movement in CAM species. The goal of this study is to identify candidate genes that could play a role in stomatal movement in an obligate CAM species, Kalanchoë fedtschenkoi . By way of a text-mining approach, proteins were identified in various plant species, spanning C 3 , C 4 , and CAM photosynthetic types, which are orthologous to proteins known to be involved in stomatal movement. A comparative analysis of diel time-course gene expression data was performed between K. fedtschenkoi and two C 3 species (i.e., Arabidopsis thaliana and Solanum lycopersicum) to identify differential gene expression between the dusk and dawn phases of the 24-h cycle. A rescheduled catalase gene known to be involved in stomatal movement was identified, suggesting a role for H 2 O 2 in CAM-like stomatal movement. Overall, these results provide new insights into the molecular regulation of stomatal movement in CAM plants, facilitating genetic improvement of drought resistance in agricultural crops through manipulation of stomata-related genes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

New insights into supradense matter from dissecting scaled stellar structure equations

The strong-field gravity in general relativity (GR) realized in neutron stars (NSs) renders the equation of state (EOS) P(ε) of supradense neutron star matter to be essentially nonlinear and refines the upper bound for Φ ≡ P/ε to be much smaller than the special relativity (SR) requirement with linear EOSs, where P and ε are respectively the pressure and energy density of the system considered. Specifically, a tight bound Φ ≲ 0.374 is obtained by perturbatively anatomizing the intrinsic structures of the scaled Tolman–Oppenheimer–Volkoff (TOV) equations without using any input nuclear EOS. New insights gained from this novel analysis provide EOS-model-independent constraints on the properties (e.g., density profiles of the sound speed squared s 2 = dP/dε and trace anomaly Δ = 1/3 – Φ) of cold supradense matter in NS cores. Using the gravity-matter duality in theories describing NSs, we investigate the impact of gravity on supradense matter EOS in NSs. In particular, we show that the NS mass M NS , radius R, and compactness ξ ≡ M NS /R scale with certain combinations of its central pressure and energy density (encapsulating its central EOS). Thus, observational data on these properties of NSs can straightforwardly constrain NS central EOSs without relying on any specific nuclear EOS model.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
DOE OSTI2026

Formation of Non-Doped Cubic Lithium Lanthanum Zirconium Oxide Nanofibers: Insights from In Situ Synchrotron X-Ray Scattering

This study investigates the formation mechanism of non-doped cubic lithium lanthanum zirconium oxide (c-LLZO) nanofibers using in situ synchrotron X-ray scattering techniques. Electrospun polymer precursor nanofibers were annealed at temperatures up to 800 °C, enabling real-time tracking of phase transitions via simultaneous small-angle X-ray scattering (SAXS), wide-angle X-ray scattering (WAXS), and evolved CO 2 gas analysis. The results reveal a three-step transformation pathway: polymer decomposition, formation of La 2 Zr 2 O 7 (LZO), and direct conversion of LZO to c-LLZO without intermediate tetragonal phases detected within the sensitivity of our in situ WAXS measurement. Cryo-electron energy loss spectroscopy (EELS) further elucidates the role of lithium diffusion, showing Li enrichment at fiber surfaces and Li deficiency in the interior, which stabilizes the cubic phase. This Li segregation effect in nanostructured LLZO materials extends beyond the previously reported size effect. This work advances the understanding of c-LLZO formation mechanisms and provides practical insights for optimizing synthesis routes to achieve phase-pure c-LLZO for solid-state battery applications.

LLZO phase stability↗
DOE OSTI2024

Structural Insights into Mechanisms Underlying Mitochondrial and Bacterial Cytochrome c Synthases

Mitochondrial holocytochrome c synthase (HCCS) is an essential protein in assembling cytochrome c (cyt c) of the electron transport system. HCCS binds heme and covalently attaches the two vinyls of heme to two cysteine thiols of the cyt c CXXCH motif. Human HCCS recognizes both cyt c and cytochrome c1 of complex III (cytochrome bc1). HCCS is mutated in some human diseases and it has been investigated recombinantly by mutational, biochemical, and reconstitution studies in the past decade. Here, we employ structural prediction programs (e.g., AlphaFold 3) on HCCS and its two substrates, heme and cytochrome c. The results, when combined with spectroscopic and functional analyses of HCCS and variants, provide insights into the structural basis for heme binding, apocyt c binding, covalent attachment, and release of the holocyt c product. Results from in vitro reconstitution of purified human HCCS using cyt c and cyt c1 peptides as acceptors are consistent with the structural modeling of substrate binding. Reconstitution of HCCS and cyt c1 provides an approach to studying cyt c1 assembly, which has been refractile to recombinant in vivo reconstitution (unlike HCCS and cyt c). We propose a structural basis for release of the holocyt c product from HCCS based on in vitro studies and on cryoEM structures of the bacterial cyt c synthase (CcsBA) active site. We analyze the kinetoplastid mitochondrial synthase (KCCS), and hypothesize a molecular evolutionary path from mitochondrial endosymbiosis to the current HCCS.

Biochemistry & Molecular Biology↗
DOE OSTI2025

Passive Acoustic Monitoring Provides Insights into Avian Use of Energycane Cropping Systems in Southern Florida

Birds are important indicators of ecosystem health and provide a range of benefits to society. It is important, therefore, to understand the impacts of agricultural land use changes on bird populations. The cultivation of energycane (EC)—a sugarcane hybrid—for biofuel production represents one form of agricultural land use change in southern Florida. We used passive acoustic monitoring (PAM) to examine bird community use of experimental EC fields and other agricultural land uses at two study sites in southern Florida. We deployed 16 acoustic recorders in different study plots and used the automatic species identifier BirdNET to identify 40 focal bird species. We found seasonal differences in daily avian species diversity and richness between EC experimental plots and reference agricultural fields (corn fields, orchards, pastureland), and between time periods (pre-planting, post-planting). Daily avian species diversity and richness were lower in the EC experimental plots during Fall and Winter months when plants reached maximum height (>400 cm in some areas). Despite seasonal differences in daily measures of species diversity and richness, we found no differences in cumulative species richness, suggesting that there may be little overall (season-long) effects of EC production. These findings could provide insight to avian seasonal habitat preferences and underscore the potential limitations of PAM in areas experiencing dynamic vegetation changes. More research is needed to better understand if utilization of EC cropping systems results in positive or negative effects on avian populations (e.g., foraging habitat quality, predator–prey dynamics, nest success).

BirdNET↗
DOE OSTI2024

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15–90. The effects of dementia, mild cognitive impairment, Parkinson’s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

Neurosciences & Neurology↗
DOE OSTI2025

Hydrothermal Liquefaction of Structurally Diverse Lignins: Insights into Biocrude Yield, Fuel Properties, and Reaction Mechanisms

Lignin holds significant promise as a feedstock for biocrude production via hydrothermal liquefaction (HTL). Although lignin HTL has been widely studied, the specific depolymerization pathways associated with distinct lignin structures remain largely unexplored. This study investigates the HTL of four structurally diverse lignins: alkaline (AL), dealkaline (DAL), organosolv (OL), and lignosulfonate (LS) across 270–310 °C to elucidate structure-specific mechanisms governing biocrude yield and composition. AL and OL achieved the highest yields (16.8 ± 0.3% and 16.8 ± 2.5%), with AL-derived biocrude showing the highest carbon content (70.2 ± 0.0%) and HHV (31.0 ± 0.2 MJ/kg). In contrast, DAL and LS produced lower yields and inferior fuel quality due to higher sulfur content and lower carbon enrichment. The structures of AL and DAL, containing fewer methoxy groups, produced guaiacol-rich biocrudes (46.6% and 69.5%). Methylation in AL formed alkyl guaiacols and veratroles, while DAL favored side-chain oxidation. OL retained complex structures, forming syringols and desaspidinol, which contributed to heavier biocrude compounds. Sulfonate groups in LS were stabilized mostly as sulfides, leading to elevated sulfur content. These findings provide mechanistic insight into how lignin structure governs HTL behavior, enabling targeted control of biocrude yield and quality for renewable fuel production.

biocrude↗
DOE OSTI2024

Transcriptomic Analysis of Arachidonic Acid Pathway Genes Provides Mechanistic Insight into Multi-Organ Inflammatory and Vascular Diseases

Arachidonic acid (AA) metabolites have been associated with several diseases across various organ systems, including the cardiovascular, pulmonary, and renal systems. Lipid mediators generated from AA oxidation have been studied to control macrophages, T-cells, cytokines, and fibroblasts, and regulate inflammatory mediators that induce vascular remodeling and dysfunction. AA is metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) to generate anti-inflammatory, pro-inflammatory, and pro-resolutory oxidized lipids. As comorbid states such as diabetes, hypertension, and obesity become more prevalent in cardiovascular disease, studying the expression of AA pathway genes and their association with these diseases can provide unique pathophysiological insights. In addition, the AA pathway of oxidized lipids exhibits diverse functions across different organ systems, where a lipid can be both anti-inflammatory and pro-inflammatory depending on the location of metabolic activity. Therefore, we aimed to characterize the gene expression of these lipid enzymes and receptors throughout multi-organ diseases via a transcriptomic meta-analysis using the Gene Expression Omnibus (GEO) Database. In our study, we found that distinct AA pathways were expressed in various comorbid conditions, especially those with prominent inflammatory risk factors. Comorbidities, such as hypertension, diabetes, and obesity appeared to contribute to elevated expression of pro-inflammatory lipid mediator genes. Our results demonstrate that expression of inflammatory AA pathway genes may potentiate and attenuate disease; therefore, we suggest further exploration of these pathways as therapeutic targets to improve outcomes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6',7'-Dihydroxybergamottin

Human cytochrome P450 3A4 (CYP3A4) is the most important drug-metabolizing enzyme. Some drugs and natural compounds can act as suicide (mechanism-based) inactivators of CYP3A4, leading to unanticipated drug-drug interactions, toxicity and therapeutic failures. Despite significant clinical and toxicological implications, the mechanism-based inactivation remains incompletely understood. This study provides the first direct insights into the interaction of CYP3A4 with three suicide substrates: mibefradil, an antihypertensive drug quickly withdrawn from the market; a semi-synthetic antibiotic azamulin; and a natural furanocoumarin, 6',7'-dihydroxybergamottin. Novel structural findings help better understand the suicide substrate binding and inhibitory mechanism, and can be used to improve the predictability of the binding ability, metabolic sites and inhibitory/inactivation potential of newly developed drugs and other chemicals relevant to public health.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Structure of Lipopolysaccharide from Liberibacter crescens Is Low Molecular Weight and Offers Insight into Candidatus Liberibacter Biology

Huanglongbing (HLB) disease, also known as citrus greening disease, was first reported in the US in 2005. Since then, the disease has decimated the citrus industry in Florida, resulting in billions of dollars in crop losses and the destruction of thousands of acres of citrus groves. The causative agent of citrus greening disease is the phloem limited pathogen Candidatus Liberibacter asiaticus. As it has not been cultured, very little is known about the structural biology of the organism. Liberibacter are part of the Rhizobiaceae family, which includes nitrogen-fixing symbionts of legumes as well as the Agrobacterium plant pathogens. To better understand the Liberibacter genus, a closely related culturable bacterium (Liberibacter crescens or Lcr) has attracted attention as a model organism for structural and functional genomics of Liberibacters. Given that the structure of lipopolysaccharides (LPS) from Gram-negative bacteria plays a crucial role in mediating host-pathogen interactions, we sought to characterize the LPS from Lcr. We found that the major lipid A component of the LPS consisted of a pentaacylated molecule with a β-6-GlcN disaccharide backbone lacking phosphate. The polysaccharide portion of the LPS was unusual compared to previously described members of the Rhizobiaceae family in that it contained ribofuranosyl residues. The LPS structure presented here allows us to extrapolate known LPS structure/function relationships to members of the Liberibacter genus which cannot yet be cultured. It also offers insights into the biology of the organism and how they manage to effectively attack citrus trees.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Insight into CAZymes of Alicyclobacillus mali FL18: Characterization of a New Multifunctional GH9 Enzyme

In the bio-based era, cellulolytic and hemicellulolytic enzymes are biocatalysts used in many industrial processes, playing a key role in the conversion of recalcitrant lignocellulosic waste biomasses. In this context, many thermophilic microorganisms are considered as convenient sources of carbohydrate-active enzymes (CAZymes). In this work, a functional genomic annotation of Alicyclobacillus mali FL18, a recently discovered thermo-acidophilic microorganism, showed a wide reservoir of putative CAZymes. Among them, a novel enzyme belonging to the family 9 of glycosyl hydrolases (GHs), named AmCel9, was identified; in-depth in silico analyses highlighted that AmCel9 shares general features with other GH9 members. The synthetic gene was expressed in Escherichia coli and the recombinant protein was purified and characterized. The monomeric enzyme has an optimal catalytic activity at pH 6.0 and has comparable activity at temperatures ranging from 40 °C to 70 °C. It also has a broad substrate specificity, a typical behavior of multifunctional cellulases; the best activity is displayed on β-1,4 linked glucans. Very interestingly, AmCel9 also hydrolyses filter paper and microcrystalline cellulose. This work gives new insights into the properties of a new thermophilic multifunctional GH9 enzyme, that looks a promising biocatalyst for the deconstruction of lignocellulose.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Three-Dimensional Structural Insights Have Revealed the Distinct Binding Interactions of Agonists, Partial Agonists, and Antagonists with the µ Opioid Receptor

The United States is experiencing the most profound and devastating opioid crisis in history, with the number of deaths involving opioids, including prescription and illegal opioids, continuing to climb over the past two decades. This severe public health issue is difficult to combat as opioids remain a crucial treatment for pain, and at the same time, they are also highly addictive. Opioids act on the opioid receptor, which in turn activates its downstream signaling pathway that eventually leads to an analgesic effect. Among the four types of opioid receptors, the µ subtype is primarily responsible for the analgesic cascade. This review describes available 3D structures of the µ opioid receptor in the protein data bank and provides structural insights for the binding of agonists and antagonists to the receptor. Comparative analysis on the atomic details of the binding site in these structures was conducted and distinct binding interactions for agonists, partial agonists, and antagonists were observed. The findings in this article deepen our understanding of the ligand binding activity and shed some light on the development of novel opioid analgesics which may improve the risk benefit balance of existing opioids.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Structural Insights into the Dynamics of Water in SOD1 Catalysis and Drug Interactions

Superoxide dismutase 1 (SOD1) is a crucial enzyme that protects cells from oxidative damage by converting superoxide radicals into H 2 O 2 and O 2 . This detoxification process, essential for cellular homeostasis, relies on a precisely orchestrated catalytic mechanism involving the copper cation, while the zinc cation contributes to the structural integrity of the enzyme. This study presents the 2.3 Å crystal structure of human SOD1 (PDB ID: 9IYK), revealing an assembly of six homodimers and twelve distinct active sites. The water molecules form a complex hydrogen-bonding network that drives proton transfer and sustains active site dynamics. Our structure also uncovers subtle conformational changes that highlight the intrinsic flexibility of SOD1, which is essential for its function. Additionally, we observe how these dynamic structural features may be linked to pathological mutations associated with amyotrophic lateral sclerosis (ALS). By advancing our understanding of hSOD1’s mechanistic intricacies and the influence of water coordination, this study offers valuable insights for developing therapeutic strategies targeting ALS. Our structure’s unique conformations and active site interactions illuminate new facets of hSOD1 function, underscoring the critical role of structural dynamics in enzyme catalysis. Moreover, we conducted a molecular docking analysis using SOD1 for potential radical scavengers and Abelson non-receptor tyrosine kinase (c-Abl, Abl1) inhibitors targeting misfolded SOD1 aggregation along with oxidative stress and apoptosis, respectively. The results showed that CHEMBL1075867, a free radical scavenger derivative, showed the most promising docking results and interactions at the binding site of hSOD1, highlighting its promising role for further studies against SOD1-mediated ALS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Restoration Insights Gained from a Field Deployment of Dithionite and Acetate at a Uranium In Situ Recovery Mine

Mining uranium by in situ recovery (ISR) typically involves injecting an oxidant and a complexing agent to mobilize and extract uranium in a saturated ore zone. This strategy involves less infrastructure and invasive techniques than traditional mining, but ISR often results in persistently elevated concentrations of U and other contaminants of concern in groundwater after mining. These concentrations may remain elevated for an extended period without remediation. Here, we describe a field experiment at an ISR facility in which both a chemical reductant (sodium dithionite) and a biostimulant (sodium acetate) were sequentially introduced into a previously mined ore zone in an attempt to establish reducing geochemical conditions that, in principle, should decrease and stabilize aqueous U concentrations. While several lines of evidence indicated that reducing conditions were established, U concentrations did not decrease, and in fact increased after the amendment deployments. We discuss likely reasons for this behavior, and we also discuss how the results provide insights into improvements that could be made to the restoration process to benefit from the seemingly detrimental behavior.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2020

Insights into the Structure and Energy of DNA Nanoassemblies

Since the pioneering work of Ned Seeman in the early 1980s, the use of the DNA molecule as a construction material experienced a rapid growth and led to the establishment of a new field of science, nowadays called structural DNA nanotechnology. Here, the self-recognition properties of DNA are employed to build micrometer-large molecular objects with nanometer-sized features, thus bridging the nano- to the microscopic world in a programmable fashion. Distinct design strategies and experimental procedures have been developed over the years, enabling the realization of extremely sophisticated structures with a level of control that approaches that of natural macromolecular assemblies. Nevertheless, our understanding of the building process, i.e., what defines the route that goes from the initial mixture of DNA strands to the final intertwined superstructure, is, in some cases, still limited. In this review, we describe the main structural and energetic features of DNA nanoconstructs, from the simple Holliday junction to more complicated DNA architectures, and present the theoretical frameworks that have been formulated until now to explain their self-assembly. Deeper insights into the underlying principles of DNA self-assembly may certainly help us to overcome current experimental challenges and foster the development of original strategies inspired to dissipative and evolutive assembly processes occurring in nature.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Mechanistic Insights into Peptide Binding and Deactivation of an Adhesion G Protein-Coupled Receptor

Adhesion G protein-coupled receptors (ADGRGs) play critical roles in the reproductive, neurological, cardiovascular, and endocrine systems. In particular, ADGRG2 plays a significant role in Ewing sarcoma cell proliferation, parathyroid cell function, and male fertility. In 2022, a cryo-EM structure was reported for the active ADGRG2 bound by an optimized peptide agonist IP15 and the Gs protein. The IP15 peptide agonist was also modified to antagonists 4PH-E and 4PH-D with mutations of the 4PH residue to Glu and Asp, respectively. However, experimental structures of inactive antagonist-bound ADGRs remain to be resolved, and the activation mechanism of ADGRs such as ADGRG2 is poorly understood. Here, we applied Gaussian accelerated molecular dynamics (GaMD) simulations to probe conformational dynamics of the agonist- and antagonist-bound ADGRG2. By performing GaMD simulations, we were able to identify important low-energy conformations of ADGRG2 in the active, intermediate, and inactive states, as well as explore the binding conformations of each peptide. Moreover, our simulations revealed critical peptide-receptor residue interactions during the deactivation of ADGRG2. In conclusion, through GaMD simulations, we uncovered mechanistic insights into peptide (agonist and antagonist) binding and deactivation of the ADGRG2. These findings will potentially facilitate rational design of new peptide modulators of ADGRG2 and other ADGRs.

59 BASIC BIOLOGICAL SCIENCES↗