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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 OSTI2017

Towards a better understanding of on and off target effects of the lymphocyte-specific kinase LCK for the development of novel and safer pharmaceuticals

In this work we have developed a multi-tiered computational platform to study protein-drug interactions. At the beginning of the workflow more efficient and less accurate methods are used to enable large libraries of proteins in many conformations and massive chemical libraries to be screened. At each subsequent step in the workflow a subset of input data is investigated with increased accuracy and more computationally expensive methods. We demonstrate the developed workflow with the investigation of the lymphocyte-specific kinase LCK, which is implicated as a drug target in many cancers and also known to have toxic effects when unintentionally targeted. Several LCK states and conformations are investigated using molecular docking and generalized Born and surface area continuum solvation (MM/GBSA). Different variations in the drug screening process provide unique results that may elucidate the biological mechanisms underlying the drug interactions.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2017

Molecular insights into the differences in anti-inflammatory activities of green tea catechins on IL-1β signaling in rheumatoid arthritis synovial fibroblasts

In this study, we found that catechins found in green tea (EGCG, EGC, and EC) differentially interfere with the IL-1β signaling pathway which regulates the expression of pro-inflammatory mediators (IL-6 and IL-8) and Cox-2 in primary human rheumatoid arthritis synovial fibroblasts (RASFs). EGCG and EGC inhibited IL-6, IL-8, and MMP-2 production and selectively inhibited Cox-2 expression. EC did not exhibit any inhibitory effects. When we looked at the expression of key signaling proteins in the IL-1β signaling pathway, we found all the tested catechins could inhibit TAK-1 activity. Therefore, the consumption of green tea offers an overall anti-inflammatory effect. Molecular docking analysis confirms that EGCG, EGC, and EC all occupy the active site of the TAK1 kinase domain. However, EGCG occupies the majority of the TAK1 active site. In addition to TAK1 inhibition, EGCG can also inhibit P38 and nuclear NF-κB expression whereas EC and EGC were not effective inhibitors. Our findings suggest one of the main health benefits associated with the consumption of green tea are due to the activity of EGCG and EGC which are both present at higher amounts. Although EGCG is the most effective catechin at inhibiting downstream inflammatory signaling, its effectiveness could be hindered by the presence of EC. Therefore, varying EC content in green tea may reduce the anti-inflammatory effects of other potential catechins in green tea. - Highlights: • Catechins EC and EGC have anti-inflammatory properties in synovial fibroblasts. • EGCG is more effective at inhibiting downstream IL-1β signaling than EGC and EC. • EC content may modify green tea's anti-inflammatory effect by competing with EGCG.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development

An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function. - Highlights: •DP2392-E10 inhibits replication of a broad range of influenza A subtypes. •DP2392-E10 inhibits nuclear exports of NP and NEP via their NP-NES3 and NEP-NES2 domains, respectively. •DP2392-E10 is predicted to directly bind CRM1 in the region near the HEAT9 and HEAT10 repeats.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

MEP pathway products allosterically promote monomerization of deoxy-D-xylulose-5-phosphate synthase to feedback-regulate their supply

Isoprenoids are a very large and diverse family of metabolites required by all living organisms. All isoprenoids derive from the double-bond isomers isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which are produced by the methylerythritol 4-phosphate (MEP) pathway in bacteria and plant plastids. It has been reported that IPP and DMAPP feedback-regulate the activity of deoxyxylulose 5-phosphate synthase (DXS), a dimeric enzyme that catalyzes the main flux-controlling step of the MEP pathway. Here we provide experimental insights into the underlying mechanism. Isothermal titration calorimetry and dynamic light scattering approaches showed that IPP and DMAPP can allosterically bind to DXS in vitro, causing a size shift. In silico ligand binding site analysis and docking calculations identified a potential allosteric site in the contact region between the two monomers of the active DXS dimer. Modulation of IPP and DMAPP contents in vivo followed by immunoblot analyses confirmed that high IPP/DMAPP levels resulted in monomerization and eventual aggregation of the enzyme in bacterial and plant cells. Loss of the enzymatically active dimeric conformation allows a fast and reversible reduction of DXS activity in response to a sudden increase or decrease in IPP/DMAPP supply, whereas aggregation and subsequent removal of monomers that would otherwise be available for dimerization appears to be a more drastic response in the case of persistent IPP/DMAPP overabundance (e.g., by a blockage in their conversion to downstream isoprenoids). Our results represent an important step toward understanding the regulation of the MEP pathway and rational design of biotechnological endeavors aimed at increasing isoprenoid contents in microbial and plant systems.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

6-Shogaol induces caspase-independent paraptosis in cancer cells via proteasomal inhibition

Highlights: • 6-Shogaol induced cytoplasmic vacuolation and death in breast and lung cancer cells. • Absence of caspase cleavage and DNA fragmentation proves its non-apoptotic nature. • Persistence of death in presence of autophagic inhibitors certifies it to be non-autophagic cell death. • It is found to inhibit the proteasome by binding to the β5 chymotrypsin subunit. • 6-Shogaol increases level of ER stress markers like Bip and CHOP in treated cancer cells. An α, β-unsaturated carbonyl compound of ginger, 6-Shogaol (6S), induced extensive cytoplasmic vacuolation and cell death in breast cancer cell (MDA-MB-231) and non-small lung cancer (A549) cells. In the presence of autophagic inhibitors the cells continued to exhibit cytoplasmic vacuolation and cell death clearly distinguishing it from the classic autophagic process. 6S induced death did not exhibit the characteristic apoptotic features like caspase cleavage, phosphatidyl serine exposure and DNA fragmentation. The immunofluorescence with the Endoplasmic Reticulum (ER) resident protein, calreticulin indicated that the vacuoles were of ER origin, typical of paraptosis. This was supported by the increase in level of microtubule associated protein light chain 3B (LC3 I and LC3 II) and polyubiquitin binding protein, p62. The level of ER stress markers like polyubiquitinated proteins, Bip and CHOP also consistently increased. We have found that 6S inhibits the 26S proteasome. The proteasomal inhibitory activity was elucidated by a) molecular docking of 6S onto the active site of β5 subunit and b) reduced fluorescence by the fluorogenic substrate of the chymotrypsin-like subunit. In conclusion these studies demonstrate for the first time that proteasomal inhibition by 6S induces cell death via paraptosis. So 6-shogaol may act as a template for anti-cancer lead discovery against the apoptosis resistant cancer cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The “transition zone” of the cilium-like regions in the Drosophila spermatocytes and the role of the C-tubule in axoneme assembly

The fruit-fly Drosophila melanogaster harbours different types of ciliary structures: ciliary projections associated with neurons of type I and cilium-like regions (CLRs) found during male gametogenesis. The latter deserve particular attention since they are morphologically similar to vertebrate primary cilia and transform into the sperm axonemes during spermiogenesis. Although, all the centrioles are able to organize the CLRs, we found that the mother centriole docks first to the plasma membrane suggesting a new intrinsic functional asymmetry between the parent centrioles. We also show that the CLRs lack the Y-links that connect the axoneme doublets with the plasma membrane in conventional primary cilia. Moreover, the C-tubules, that are lacking in the axoneme of the primary cilia, persisted along the CLRs albeit modified into longitudinal blades. Remarkably, mutant flies in which the CLRs are devoid of the C-tubules or their number is reduced lack sperm axonemes or have incomplete axonemes. Therefore, the C-tubules are dispensable for the assembly of the CLRs but are essential for sperm axoneme elongation and maintenance in Drosophila.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Identification of protein/mRNA network involving the PSORS1 locus gene CCHCR1 and the PSORS4 locus gene HAX1

Highlights: • CCHCR1 and HAX1 proteins directly interact. • CCHCR1 is a psoriasis candidate gene located on PSORS1 locus. • HAX1 gene is located on PSORS4 locus and is overexpressed in psoriasis. • CCHCR1 and HAX1 co-localize with and affect specific mRNAs in vesicles. • Novel protein/mRNA networks involving CCHCR1 and HAX1 could play a role in psoriasis. CCHCR1 (Coiled-Coil alpha-Helical Rod 1), maps to chromosomal region 6p21.3, within the major psoriasis susceptibility locus PSORS1. CCHCR1 itself is a plausible psoriasis candidate gene, however its role in psoriasis pathogenesis remains unclear. We previously demonstrated that CCHCR1 protein acts as a cytoplasmic docking site for RNA polymerase II core subunit 3 (RPB3) in cycling cells, suggesting a role for CCHCR1 in vesicular trafficking between cellular compartments. Here, we report a novel interaction between CCHCR1 and the RNA binding protein HAX1. HAX1 maps to chromosomal region 1q21.3 within the PSORS4 locus and is over-expressed in psoriasis. Both CCHCR1 and HAX1 share subcellular co-localization with mitochondria, nuclei and cytoplasmic vesicles as P-bodies. By a series of ribonucleoprotein immunoprecipitation (RIP) assays, we isolated a pool of mRNAs complexed with HAX1 and/or CCHCR1 proteins. Among the mRNAs complexed with both CCHCR1 and HAX1 proteins, there are Vimentin mRNA, previously described to be bound by HAX1, and CAMP/LL37 mRNA, whose gene product is over-expressed in psoriasis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Hydrogen-Bonded Organic Frameworks: A Rising Class of Porous Molecular Materials

Hydrogen-bonded organic frameworks (HOFs) are a class of porous molecular materials that rely on the assembly of organic building blocks by means of hydrogen-bonding interactions to form two-dimensional (2D) and three-dimensional (3D) crystalline networks. The reversible nature of the hydrogen-bond formation endows HOFs with the attributes of solution processability and simple regeneration. High-quality single crystals of HOFs can be grown easily for unambiguous superstructure determination by single-crystal X-ray diffraction, which is crucial for the elucidation of superstructure–property relationships. During the past decade, considerable progress has been achieved in realizing stable HOFs with permanent porosities by focusing on the design of molecular building blocks in order to introduce rigidity, auxiliary [π···π] interactions, and interpenetration of their frameworks to sustain the extended networks. The applications of HOFs are far-reaching, spanning catalysis, energy, and biomedical products as well as the storage and separation of fine chemicals. In this paper, we, first of all, provide an overview of the chronological development of HOFs, starting from the seminal work by Marsh and Duchamp in 1969 on the crystal superstructure of the hydrogen-bonded networks of trimesic acid. We identify the development of novel hydrogen-bonding motifs such as diaminotriazine (DTA), the introduction of the concept of molecular tectonics, and the establishment of permanent porosity in HOFs as being some of the milestones, which incentivized the current burgeoning research endeavors on developing HOFs as multifunctional materials. This Account is focused primarily on surveying the strategies for constructing porous 3D HOFs based on organic building blocks with peripheral carboxyl groups. These strategies are presented in the following categories: (1) the polycatenation of 2D networks by trigonal building blocks to form global 3D frameworks, (2) the utilization of building blocks with 3D geometries—tetrahedral and trigonal prismatic—that are predisposed to form 3D networks, and (3) the docking by shape-fitting of geometrically labile building blocks. We emphasize how the molecular geometry of the building blocks plays an important role in modulating the superstructures of extended frameworks so as to address specific applications. Recognizing that the in silico design of HOFs is the ultimate goal of researchers in this field, we also discuss the recent advances in superstructure prediction that lead to the formation of porous supramolecular crystals and assess the complications in implementing computational methods for HOFs with complex superstructures. We hope this Account will inspire the development of new supramolecular designs and creative approaches to crystal engineering that aid and abet the assembly of multifunctional HOFs with customizable properties.

36 MATERIALS SCIENCE↗
DOE OSTI2017

Smart Self-Assembled Organic Nanoprobe for Protein-Specific Detection: Design, Synthesis, Application, and Mechanism Studies

Specific detection or imaging protein has high potential to contribute greatly to medical diagnosis, biological research, and therapeutic applications. The level of human serum albumin (HSA) in blood is related to a variety of diseases and thus serves as an important biomarker for fast clinical diagnosis. In this paper we report the use of aggregation-induced emission (AIE) based supramolecular assembly to design biomolecular responsive smart organic nanomaterials for detection protein HSA. The designed nanoprobes were aggregates of small molecules and silent in fluorescence, but in the presence of HSA they disassembled and produced a clear turn-on fluorescent signal. Of a small library of nanoprobes constructed for HSA detection, structure-optical signaling and screening studies revealed that nanoprobe 7 is the most efficient one. Mechanism studies showed that nanoprobe 7 was bonded with Site I of HSA through the multiple noncovalent interactions. The resultant restriction of intramolecular rotation of nanoprobe 7 in the hydrophobic cavity of HSA induced fluorescent emission, which was validated by competitive binding assays and molecular docking. More importantly, nanoprobe 7 was successfully applied to recognize and quantify HSA in human serum samples. This study demonstrates nanoprobe 7 is a promising tool for clinical real and fast detection of HSA and thus may find many applications, and the molecular assembly based on AIE also opens a new avenue for designing smart nanomaterials for the sensitive and selective detection for varied analytes.

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

Design of Diverse Asymmetric Pockets in De Novo Homo-oligomeric Proteins

A challenge for design of protein–small-molecule recognition is that incorporation of cavities with size, shape, and composition suitable for specific recognition can considerably destabilize protein monomers. This challenge can be overcome through binding pockets formed at homo-oligomeric interfaces between folded monomers. Interfaces surrounding the central homo-oligomer symmetry axes necessarily have the same symmetry and so may not be well suited to binding asymmetric molecules. To enable general recognition of arbitrary asymmetric substrates and small molecules, we developed an approach to designing asymmetric interfaces at off-axis sites on homo-oligomers, analogous to those found in native homo-oligomeric proteins such as glutamine synthetase. We symmetrically dock curved helical repeat proteins such that they form pockets at the asymmetric interface of the oligomer with sizes ranging from several angstroms, appropriate for binding a single ion, to up to more than 20 Å across. Of the 133 proteins tested, 84 had soluble expression in E. coli, 47 had correct oligomeric states in solution, 35 had small-angle X-ray scattering (SAXS) data largely consistent with design models, and 8 had negative-stain electron microscopy (nsEM) 2D class averages showing the structures coming together as designed. Both an X-ray crystal structure and a cryogenic electron microscopy (cryoEM) structure are close to the computational design models. The nature of these proteins as homo-oligomers allows them to be readily built into higher-order structures such as nanocages, and the asymmetric pockets of these structures open rich possibilities for small-molecule binder design free from the constraints associated with monomer destabilization.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

The Conformational Change in Elongation Factor Tu Involves Separation of Its Domains

Elongation factor Tu (EF-Tu) is a highly conserved GTPase that is responsible for supplying the aminoacylated tRNA to the ribosome. Upon binding to the ribosome, EF-Tu undergoes GTP hydrolysis, which drives a major conformational change, triggering the release of aminoacylated tRNA to the ribosome. Using a combination of molecular simulation techniques, we studied the transition between the pre- and post-hydrolysis structures through two distinct pathways. Here, we show that the transition free energy is minimal along a non-intuitive pathway that involves “separation” of the GTP binding domain (domain 1) from the OB folds (domains 2 and 3), followed by domain 1 rotation, and, eventually, locking the EF-Tu conformation in the post-hydrolysis state. The domain separation also leads to a slight extension of the linker connecting domain 1 to domain 2. Using docking tools and correlation-based analysis, we identified and characterized the EF-Tu conformations that release the tRNA. These calculations suggest that EF-Tu can release the tRNA before the domains separate and after domain 1 rotates by 25°. Lastly, we also examined the EF-Tu conformations in the context of the ribosome. Given the high degrees of sequence similarity with other translational GTPases, we predict a similar separation mechanism is followed.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Biochemical Characterization and Structure-Based Mutational Analysis Provide Insight into the Binding and Mechanism of Action of Novel Aspartate Aminotransferase Inhibitors

Pancreatic cancer cells are characterized by deregulated metabolic programs that facilitate growth and resistance to oxidative stress. Among these programs, pancreatic cancers preferentially utilize a metabolic pathway through the enzyme aspartate aminotransferase 1 [also known as glutamate oxaloacetate transaminase 1 (GOT1)] to support cellular redox homeostasis. As such, small molecule inhibitors that target GOT1 could serve as starting points for the development of new therapies for pancreatic cancer. We ran a high-throughput screen for inhibitors of GOT1 and identified a small molecule, iGOT1-01, with in vitro GOT1 inhibitor activity. Application in pancreatic cancer cells revealed metabolic and growth inhibitory activity reflecting a promiscuous inhibitory profile. We then performed an in silico docking analysis to study inhibitor–GOT1 interactions with iGOT1-01 analogues that possess improved solubility and potency properties. Here, these results suggested that the GOT1 inhibitor competed for binding to the pyridoxal 5-phosphate (PLP) cofactor site of GOT1. To analyze how the GOT1 inhibitor bound to GOT1, a series of GOT1 mutant enzymes that abolished PLP binding were generated. Application of the mutants in X-ray crystallography and thermal shift assays again suggested but were unable to formally conclude that the GOT1 inhibitor bound to the PLP site. Mutational studies revealed the relationship between PLP binding and the thermal stability of GOT1 while highlighting the essential nature of several residues for GOT1 catalytic activity. Insight into the mode of action of GOT1 inhibitors may provide leads to the development of drugs that target redox balance in pancreatic cancer.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2019

Structural and Functional Characterization of YdjI, an Aldolase of Unknown Specificity in Escherichia coli K12

The ydj gene cluster is found in 80% of sequenced Escherichia coli genomes and other closely related species in the human microbiome. On the basis of the annotations of the enzymes located in this cluster, it is expected that together they catalyze the catabolism of an unknown carbohydrate. The focus of this investigation is on YdjI, which is in the ydj gene cluster of E. coli K-12. It is predicted to be a class II aldolase of unknown function. Here we describe a structural and functional characterization of this enzyme. YdjI catalyzes the hydrogen/deuterium exchange of the pro- S hydrogen at C3 of dihydroxyacetone phosphate (DHAP). In the presence of DHAP, YdjI catalyzes an aldol condensation with a variety of aldo sugars. YdjI shows a strong preference for higher-order (seven-, eight-, and nine-carbon) monosaccharides with specific hydroxyl stereochemistries and a negatively charged terminus (carboxylate or phosphate). The best substrate is l -arabinuronic acid with an apparent k cat of 3.0 s –1 . The product, l - glycero - l - galacto -octuluronate-1-phosphate, has a k cat / K m value of 2.1 × 10 3 M –1 s –1 in the retro-aldol reaction with YdjI. This is the first recorded synthesis of l - glycero - l - galacto -octuluronate-1-phosphate and six similar carbohydrates. The crystal structure of YdjI, determined to a nominal resolution of 1.75 Å (Protein Data Bank entry 6OFU ), reveals unusual positions for two arginine residues located near the active site. Furthermore, computational docking was utilized to distinguish preferable binding orientations for l - glycero - l - galacto -octuluronate-1-phosphate. These results indicate a possible alternative binding orientation for l - glycero - l - galacto -octuluronate-1-phosphate compared to that observed in other class II aldolases, which utilize shorter carbohydrate molecules.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2017

Structural, Chemical, and Dynamical Frustration: Origins of Superionic Conductivity in closo -Borate Solid Electrolytes

Li 2 B 12 H 12 , Na 2 B 12 H 12 , and their closo-borate relatives exhibit unusually high ionic conductivity, making them attractive as a new class of candidate electrolytes in solid-state Li- and Na-ion batteries. However, further optimization of these materials requires a deeper understanding of the fundamental mechanisms underlying ultrafast ion conduction. To this end, we use ab initio molecular dynamics simulations and density-functional calculations to explore the motivations for cation diffusion. We find that superionic behavior in Li 2 B 12 H 12 and Na 2 B 12 H 12 results from a combination of key structural, chemical, and dynamical factors that introduce intrinsic frustration and disorder. A statistical metric is used to show that the structures exhibit a high density of accessible interstitial sites and site types, which correlates with the flatness of the energy landscape and the observed cation mobility. Furthermore, cations are found to dock to specific anion sites, leading to a competition between the geometric symmetry of the anion and the symmetry of the lattice itself, which can facilitate cation hopping. Finally, facile anion reorientations and other low-frequency thermal vibrations lead to fluctuations in the local potential that enhance cation mobility by creating a local driving force for hopping. In conclusion, we discuss the relevance of each factor for developing new ionic conductivity descriptors that can be used for discovery and optimization of closo-borate solid electrolytes, as well as superionic conductors more generally.

25 ENERGY STORAGE↗
DOE OSTI2022

In-Use Passenger Vessel Emission Rates of Black Carbon and Nitrogen Oxides

This study quantified emission factors of black carbon (BC) and nitrogen oxides (NO x ) from 21 engines on in-use excursion vessels and ferries operating in California's San Francisco Bay, including EPA uncertified and Tier 1-4 engines and across engine operating modes. On average, ~60 fuel-based emission factors per engine were measured using a novel combination of exhaust plume capture combined with GPS location and speed data that can be more readily deployed than common portable emissions measurement systems. Here, BC and NO x emission factors (g kg -1 ) were lowest and least variable during fast cruising and highest during maneuvering and docked operation. Selective catalytic reduction (SCR) reduced NO x emissions by ~80% when functional. However, elevated NO x emissions that exceeded corresponding exhaust standards were measured on most Tier 3 and Tier 4 engines sampled, which can be attributed to inactive SCR during frequent low engine load operation. In contrast, BC emissions exceeded the PM emission standard for only one engine, and SCR systems employed as a NO x reduction technology also reduced emitted BC. Using these measured emission factors to compare commuting options, we show that the CO 2 -equivalent emissions per passenger-kilometer are comparable when commuting by car and ferry, but BC and NO x emissions can be several to more than ten times larger when commuting by ferry.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

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

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

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

CoarsenConf: Equivariant Coarsening with Aggregated Attention for Molecular Conformer Generation

Molecular conformer generation (MCG) is an important task in cheminformatics and drug discovery. The ability to efficiently generate low-energy 3D structures can avoid expensive quantum mechanical simulations, leading to accelerated virtual screenings and enhanced structural exploration. Several generative models have been developed for MCG, but many struggle to consistently produce high-quality conformers for meaningful downstream applications. To address these issues, we introduce CoarsenConf, which coarse-grains molecular graphs based on torsional angles and integrates them into an SE(3)-equivariant hierarchical variational autoencoder. Through equivariant coarse-graining, we aggregate the fine-grained atomic coordinates of subgraphs connected via rotatable bonds, creating a variable-length coarse-grained latent representation. Our model uses a novel aggregated attention mechanism to restore fine-grained coordinates from the coarse-grained latent representation, enabling efficient generation of accurate conformers. Furthermore, we evaluate the chemical and biochemical quality of our generated conformers on multiple downstream applications, including property prediction and large-scale oracle-based protein docking. Overall, CoarsenConf generates more accurate conformer ensembles compared to prior generative models.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗