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At least 271 records · Page 15

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DOE OSTI2023

The molecular basis of the neutralization breadth of the RBD-specific antibody CoV11

SARS-CoV-2, the virus behind the COVID-19 pandemic, has changed over time to the extent that the current virus is substantially different from what originally led to the pandemic in 2019–2020. Viral variants have modified the severity and transmissibility of the disease and continue do so. How much of this change is due to viral fitness versus a response to immune pressure is hard to define. One class of antibodies that continues to afford some level of protection from emerging variants are those that closely overlap the binding site for angiotensin-converting enzyme 2 (ACE2) on the receptor binding domain (RBD). Some members of this class that were identified early in the course of the pandemic arose from the VH 3-53 germline gene (IGHV3-53*01) and had short heavy chain complementarity-determining region 3s (CDR H3s). Here, we describe the molecular basis of the SARS-CoV-2 RBD recognition by the anti-RBD monoclonal antibody CoV11 isolated early in the COVID-19 pandemic and show how its unique mode of binding the RBD determines its neutralization breadth. CoV11 utilizes a heavy chain VH 3-53 and a light chain VK 3-20 germline sequence to bind to the RBD. Two of CoV11’s four heavy chain changes from the VH 3-53 germline sequence, $Thr^{28}_{FWRH1}$ to Ile and $Ser^{31}_{CDRH1}$ to Arg, and some unique features in its CDR H3 increase its affinity to the RBD, while the four light chain changes from the VK 3-20 germline sequence sit outside of the RBD binding site. Antibodies of this type can retain significant affinity and neutralization potency against variants of concern (VOCs) that have diverged significantly from original virus lineage such as the prevalent omicron variant. We also discuss the mechanism by which VH 3-53 encoded antibodies recognize spike antigen and show how minimal changes to their sequence, their choice of light chain, and their mode of binding influence their affinity and impact their neutralization breadth.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Stable binding to phosphatidylserine-containing membranes requires conserved arginine residues in tandem C domains of blood coagulation factor VIII

At sites of vascular damage, factor VIII (fVIII) is proteolytically activated by thrombin and binds to activated platelet surfaces with activated factor IX (fIXa) to form the intrinsic “tenase” complex. Previous structural and mutational studies of fVIII have identified the C1 and C2 domains in binding to negatively charged membrane surfaces through β-hairpin loops with solvent-exposed hydrophobic residues and a ring of positively charged basic residues. Several hemophilia A-associated mutations within the C domains are suggested to disrupt lipid binding, preventing formation of the intrinsic tenase complex. In this study, we devised a novel platform for generating recombinant C1, C2, and C1C2 domain constructs and performed mutagenesis of several charged residues proximal to the putative membrane binding region of each C domain. Binding measurements between phosphatidylserine (PS)-containing lipid membrane surfaces and fVIII C domains demonstrated an ionic strength dependence on membrane binding affinity. Mutations to basic residues adjacent to the surface-exposed hydrophobic regions of C1 and C2 differentially disrupted membrane binding, with abrogation of binding occurring for mutations to conserved arginine residues in the C1 (R2163) and C2 (R2320) domains. Lastly, we determined the X-ray crystal structure of the porcine fVIII C2 domain bound to o-phospho-L-serine, the polar headgroup of PS, which binds to a basic cleft and makes charge-charge contact with R2320. We conclude that basic clefts in the fVIII C domains bind to PS-containing membranes through conserved arginine residues via a C domain modularity, where each C domain possesses modest electrostatic-dependent affinity and tandem C domains are required for high affinity binding.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

The His-tag as a decoy modulating preferred orientation in cryoEM

The His-tag is a widely used affinity tag that facilitates purification by means of affinity chromatography of recombinant proteins for functional and structural studies. We show here that His-tag presence affects how coproheme decarboxylase interacts with the air-water interface during grid preparation for cryoEM. Depending on His-tag presence or absence, we observe significant changes in patterns of preferred orientation. Our analysis of particle orientations suggests that His-tag presence can mask the hydrophobic and hydrophilic patches on a protein’s surface that mediate the interactions with the air-water interface, while the hydrophobic linker between a His-tag and the coding sequence of the protein may enhance other interactions with the air-water interface. Our observations suggest that tagging, including rational design of the linkers between an affinity tag and a protein of interest, offer a promising approach to modulating interactions with the air-water interface.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Enhancing Paraoxon Binding to Organophosphorus Hydrolase Active Site

Organophosphorus hydrolase (OPH) is a metalloenzyme that can hydrolyze organophosphorus agents resulting in products that are generally of reduced toxicity. The best OPH substrate found to date is diethyl p-nitrophenyl phosphate (paraoxon). Most structural and kinetic studies assume that the binding orientation of paraoxon is identical to that of diethyl 4-methylbenzylphosphonate, which is the only substrate analog co-crystallized with OPH. In the current work, we used a combined docking and molecular dynamics (MD) approach to predict the likely binding mode of paraoxon. Then, we used the predicted binding mode to run MD simulations on the wild type (WT) OPH complexed with paraoxon, and OPH mutants complexed with paraoxon. Additionally, we identified three hot-spot residues (D253, H254, and I255) involved in the stability of the OPH active site. We then experimentally assayed single and double mutants involving these residues for paraoxon binding affinity. The binding free energy calculations and the experimental kinetics of the reactions between each OPH mutant and paraoxon show that mutated forms D253E, D253E-H254R, and D253E-I255G exhibit enhanced substrate binding affinity over WT OPH. Interestingly, our experimental results show that the substrate binding affinity of the double mutant D253E-H254R increased by 19-fold compared to WT OPH.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2023

Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice

Positron emission tomography (PET) radioligands that bind with high-affinity to α4β2-type nicotinic receptors (α4β2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and the cerebellum for kinetic analysis of radioligand binding in mice. Two radioligands were explored: 2-[ 18 F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [ 18 F]Nifene, displaying similar pKa and binding affinity to nicotine. Time–activity curves of the left ventricle of the heart displayed similar distribution across wild type mice, mice lacking the β2-subunit for ligand binding, and acute nicotine-treated mice, whereas reference tissue binding displayed high variation between groups. Binding potential estimated from a two-tissue compartment model fit of the data with the image-derived input function were higher than estimates from reference tissue-based estimations. Rate constants of radioligand dissociation were very slow for 2-FA and very fast for Nifene. We conclude that using an image-derived input function for kinetic modeling of nicotinic PET ligands provides suitable results compared to reference tissue-based methods and that the chemical properties of 2-FA and Nifene are suitable to study receptor response to nicotine addiction and smoking cessation therapies.

2-FA85380↗

DOE OSTI2024

Mobile barrier mechanisms for Na + -coupled symport in an MFS sugar transporter

While many 3D structures of cation-coupled transporters have been determined, the mechanistic details governing the obligatory coupling and functional regulations still remain elusive. The bacterial melibiose transporter (MelB) is a prototype of major facilitator superfamily transporters. With a conformation-selective nanobody, we determined a low-sugar affinity inward-facing Na + -bound cryoEM structure. The available outward-facing sugar-bound structures showed that the N- and C-terminal residues of the inner barrier contribute to the sugar selectivity. The inward-open conformation shows that the sugar selectivity pocket is also broken when the inner barrier is broken. Isothermal titration calorimetry measurements revealed that this inward-facing conformation trapped by this nanobody exhibited a greatly decreased sugar-binding affinity, suggesting the mechanisms for substrate intracellular release and accumulation. While the inner/outer barrier shift directly regulates the sugar-binding affinity, it has little or no effect on the cation binding, which is supported by molecular dynamics simulations. Furthermore, the hydron/deuterium exchange mass spectrometry analyses allowed us to identify dynamic regions; some regions are involved in the functionally important inner barrier-specific salt-bridge network, which indicates their critical roles in the barrier switching mechanisms for transport. These complementary results provided structural and dynamic insights into the mobile barrier mechanism for cation-coupled symport.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Methods and materials for determination of distribution coefficients for separation materials

Methods and materials for determining the affinity of separation materials for targeted species are described. A composite separation medium is described that combines a separation material such as an ion exchange material or a sorbent with an SERS substrate. Methods and materials can be utilized to determine the distribution coefficient of a species for a separation material after running a single separation protocol followed by examination of the separation material of the protocol according to SERS. Disclosed methods can be utilized to determine the affinity of existing separation materials for targeted species as well as to determine the affinity of newly engineered separation materials to characterize species.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

DOE OSTI2024

Synergetic Effects of Soil Organic Matter Components During Interactions with Minerals

Mineral-associated soil organic matter (SOM) is critical for stabilizing organic carbon and mitigating climate change. However, mineral-SOM interactions at the molecular scale, particularly synergetic adsorption through organic-organic interaction on the mineral surface known as organic multilayering, remain poorly understood. This study investigates the impact of organic multilayering on mineral-SOM interactions, by integrating macroscale experiments and molecular-scale simulations that assess the individual and sequential adsorption of major SOM compounds – lauric acid (lipid), pentaglycine (amino acid), trehalose (carbohydrate), and lignin onto soil minerals. Ferrihydrite, Al-hydroxide, and calcite are exposed to SOM compounds to determine adsorption affinities and binding energies. Results show that lauric acid has 20-40 times higher K d than pentaglycine, following the order K d (ferrihydrite) > K d (Al-hydroxide) >> K d (calcite). Molecular-scale simulations confirm that lauric acid has a higher binding energy (30.8 kcal/mol) on ferrihydrite than pentaglycine (6.0 kcal/mol), attributed to lipid hydrophobicity. The lower binding energy of pentaglycine results from its hydrophilic amide groups, facilitating partitioning into water. Sequential experiments examine how the first layer of lipid or amino acid affects the adsorption of carbohydrate/lignin, which show little or no individual adsorption affinities. Macroscale results reveal that lipid and amino acid adsorption induce ferrihydrite particle repulsion increasing reactive surface area and enhancing carbohydrate/lignin adsorption independently and synergistically through organic multilayering. Molecular-scale results reveal that amino acid adsorbed on ferrihydrite interacts more readily with lignin macroaggregates (preformed in solution) than with individual lignin units, indicating organic multilayering via H-bonding. Further, these findings reveal the molecular mechanisms of SOM-mineral interactions, crucial for enhancing soil carbon stabilization.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2020

Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody

Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. However, vaccine design is complicated by concern that elicited antibodies (Abs) may cross-react with other flaviviruses that share a similar envelope protein, such as dengue virus, West Nile virus, and yellow fever virus. This cross-reactivity may worsen symptoms of a subsequent infection through Ab-dependent enhancement. To better understand the neutralizing Ab response and risk of Ab-dependent enhancement, further information on germline Ab binding to ZIKV and the maturation process that gives rise to potently neutralizing Abs is needed. In this work, we use binding and structural studies to compare mature and inferred-germline Ab binding to envelope protein domain III of ZIKV and other flaviviruses. We show that affinity maturation of the light-chain variable domain is important for strong binding of the recurrent VH3-23/VK1-5 neutralizing Abs to ZIKV envelope protein domain III, and identify interacting residues that contribute to weak, cross-reactive binding to West Nile virus. These findings provide insight into the affinity maturation process and potential cross-reactivity of VH3-23/VK1-5 neutralizing Abs, informing precautions for protein-based vaccines designed to elicit germline versions of neutralizing Abs.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Top Stack Optimization for Cu 2 BaSn(S, Se) 4 Photovoltaic Cell Leads to Improved Device Power Conversion Efficiency beyond 6%

Earth-abundant and air-stable Cu 2 BaSnS 4-x Se x (CBTSSe) and related thin-film absorbers are regarded as prospective options to meet the increasing demand for low-cost solar cell deployment. Devices based on vacuum-deposited CBTSSe absorbers have achieved record power conversion efficiency (PCE) of 5.2 % based on a conventional device structure using CdS buffer and i-ZnO/ITO window layers, with open-circuit voltage (V OC ) posing the major bottleneck for improving solar cell performance. The current study demonstrates a >20 % improvement in V OC (from 0.62 V to 0.75 V) and corresponding enhancement in PCE (from 5.1 % to 6.2 % without anti-reflection coating; to 6.5 % with MgF 2 anti-reflection coating) for solution-deposited CBTSSe solar cells. This performance improvement is realized by introducing an alternative successive ionic layer adsorption and reaction (SILAR)-deposited Zn 1-x Cd x S buffer combined with sputtered Zn 1-x Mg x O/Al-doped ZnO window/top contact layer, which offer lower electron affinities relative to the conventional CdS/i-ZnO/ITO stack and better matching with the low electron affinity of CBTSSe. A combined experimental (temperature- and light intensity-dependent V OC measurements) and device simulation (SCAPS-1D) evaluation points to the importance of addressing relative band offsets for both the buffer and window layers relative to the absorber in mitigating interfacial recombination and optimizing CBTSSe solar cell performance.

25 ENERGY STORAGE↗

DOE OSTI2020

Sulfonyl PIM–1: A diverse separation membrane with dilation resistance

A sulfone modified variant (soPIM–1) of the first polymer of intrinsic microporosity has been studied through molecular simulations to analyze its applicability for adsorption–based separations of diverse nonpolar, quadrupolar, and dipolar adsorbate species. Single component gas phase adsorption isotherms of each adsorbate are provided. Here, the adsorptive properties of soPIM–1 are reported from the application of two methods: (a) traditional grand canonical Monte Carlo (GCMC) simulations and (b) a combination of Monte Carlo and molecular dynamics (GCMC/MD) techniques, which accounts for sorption–induced polymer dynamics. The calculated isosteric heats of adsorption are compared to those from the parent PIM–1 structure and reveals increased CO2 affinity with relatively no change in hydrocarbon affinity. Moreover, to quantify soPIM–1's resistance to dilation the evolution of the microporous structure across the adsorption isotherm loading pressures has been evaluated. Relatedly, nonequilibrium MD simulations have been utilized to determine that soPIM–1 is approximately twice as stiff as PIM–1.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2022

CO 2 Capture by Hybrid Ultramicroporous TIFSIX‐3‐Ni under Humid Conditions Using Non‐Equilibrium Cycling

Abstract Although pyrazine‐linked hybrid ultramicroporous materials (HUMs, pore size <7 Å) are benchmark physisorbents for trace carbon dioxide (CO 2 ) capture under dry conditions, their affinity for water (H 2 O) mitigates their carbon capture performance in humid conditions. Herein, we report on the co‐adsorption of H 2 O and CO 2 by TIFSIX‐3‐Ni—a high CO 2 affinity HUM—and find that slow H 2 O sorption kinetics can enable CO 2 uptake and release using shortened adsorption cycles with retention of ca. 90 % of dry CO 2 uptake. Insight into co‐adsorption is provided by in situ infrared spectroscopy and ab initio calculations. The binding sites and sorption mechanisms reveal that both CO 2 and H 2 O molecules occupy the same ultramicropore through favorable interactions between CO 2 and H 2 O at low water loading. An energetically favored water network displaces CO 2 molecules at higher loading. Our results offer bottom‐up design principles and insight into co‐adsorption of CO 2 and H 2 O that is likely to be relevant across the full spectrum of carbon capture sorbents to better understand and address the challenge posed by humidity to gas capture.

Ullah, Saif↗

DOE OSTI2025

Catching Fullerenes: Synthesis of Molecular Nanogloves

Abstract Herein, we report the synthesis of a new series of rigid, all meta ‐phenylene, conjugated deep‐cavity molecules, displaying high binding affinity towards buckyballs. A facile synthetic approach with an overall combined yield of approximately 53% in the last two steps has been developed using a templating strategy that combines the general structure of resorcin[4]arene and [12]cyclo‐ meta ‐phenylene. These two moieties are covalently linked via four acetal bonds, resulting in a glove‐like architecture. 1 H NMR titration experiments reveal fullerene binding affinities ( K a ) exceeding ≥10 6 M −1 . The size complementarity between fullerenes and these scaffolds maximizes CH⋯π and π⋯π interactions, and their host:guest adduct resembles a ball in a glove, hence their name as nanogloves. Fullerene recognition is tested by suspending carbon soot in a solution of nanoglove in 1,1,2,2‐tetrachloroethane, where more than a dozen fullerenes are observed, ranging from C 60 to C 96 .

Mirzaei, Saber [Department of Chemistry Rice Unive↗

DOE OSTI2022

CO 2 Capture by Hybrid Ultramicroporous TIFSIX‐3‐Ni under Humid Conditions Using Non‐Equilibrium Cycling

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2024

Chelator‐Assisted Precipitation‐Based Separation of the Rare Earth Elements Neodymium and Dysprosium from Aqueous Solutions

The rare earth elements (REEs) are critical resources for many clean energy technologies, but are difficult to obtain in their elementally pure forms because of their nearly identical chemical properties. Here, an analogue of macropa, G-macropa, was synthesized and employed for an aqueous precipitation-based separation of Nd 3+ and Dy 3+ . G-macropa maintains the same thermodynamic preference for the large REEs as macropa, but shows smaller thermodynamic stability constants. Molecular dynamics studies demonstrate that the binding affinity differences of these chelators for Nd 3+ and Dy 3+ is a consequence of the presence or absence of an inner-sphere water molecule, which alters the donor strength of the macrocyclic ethers. Leveraging the small REE affinity of G-macropa, we demonstrate that within aqueous solutions of Nd 3+ , Dy 3+ , and G-macropa, the addition of HCO 3 − selectively precipitates Dy 2 (CO 3 ) 3 , leaving the Nd 3+ −G-macropa complex in solution. With this method, remarkably high separation factors of 841 and 741 are achieved for 50 : 50 and 75 : 25 mixtures. Further studies involving Nd 3+ :Dy 3+ ratios of 95 : 5 in authentic magnet waste also afford an efficient separation as well. Finally, G-macropa is recovered via crystallization with HCl and used for subsequent extractions, demonstrating its good recyclability.

Gao, Yangyang↗

DOE OSTI2020

Identification of preferred multimodal ligand‐binding regions on IgG1 F C using nuclear magnetic resonance and molecular dynamics simulations

Abstract In this study, the binding of multimodal chromatographic ligands to the IgG1 F C domain were studied using nuclear magnetic resonance and molecular dynamics simulations. Nuclear magnetic resonance experiments carried out with chromatographic ligands and a perdeuterated 15 N‐labeled F C domain indicated that while single‐mode ion exchange ligands interacted very weakly throughout the F C surface, multimodal ligands containing negatively charged and aromatic moieties interacted with specific clusters of residues with relatively high affinity, forming distinct binding regions on the F C . The multimodal ligand‐binding sites on the F C were concentrated in the hinge region and near the interface of the C H 2 and C H 3 domains. Furthermore, the multimodal binding sites were primarily composed of positively charged, polar, and aliphatic residues in these regions, with histidine residues exhibiting some of the strongest binding affinities with the multimodal ligand. Interestingly, comparison of protein surface property data with ligand interaction sites indicated that the patch analysis on F C corroborated molecular‐level binding information obtained from the nuclear magnetic resonance experiments. Finally, molecular dynamics simulation results were shown to be qualitatively consistent with the nuclear magnetic resonance results and to provide further insights into the binding mechanisms. An important contribution to multimodal ligand‐F C binding in these preferred regions was shown to be electrostatic interactions and π–π stacking of surface‐exposed histidines with the ligands. This combined biophysical and simulation approach has provided a deeper molecular‐level understanding of multimodal ligand–F C interactions and sets the stage for future analyses of even more complex biotherapeutics.

Gudhka, Ronak B.↗

DOE OSTI2020

Reduced type-A carbohydrate-binding module interactions to cellulose I leads to improved endocellulase activity

Dissociation of nonproductively bound cellulolytic enzymes from cellulose is hypothesized to be a key rate-limiting factor impeding cost-effective biomass conversion to fermentable sugars. However, the role of carbohydrate-binding modules (CBMs) in enabling nonproductive enzyme binding is not well understood. Here, we examine the subtle interplay of CBM binding and cellulose hydrolysis activity for three models type-A CBMs (Families 1, 3a, and 64) tethered to multifunctional endoglucanase (CelE) on two distinct cellulose allomorphs (i.e., cellulose I and III). We generated a small library of mutant CBMs with varying cellulose affinity, as determined by equilibrium binding assays, followed by monitoring cellulose hydrolysis activity of CelE–CBM fusion constructs. Finally, kinetic binding assays using quartz crystal microbalance with dissipation were employed to measure CBM adsorption and desorption rate constants kon and koff, respectively, towards nanocrystalline cellulose derived from both allomorphs. Overall, our results indicate that reduced CBM equilibrium binding affinity towards cellulose I alone, resulting from increased desorption rates (koff) and reduced effective adsorption rates (nkon), is correlated to overall improved endocellulase activity. Future studies could employ similar approaches to unravel the role of CBMs in nonproductive enzyme binding and develop improved cellulolytic enzymes for industrial applications.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

A Route to Design Novel Functional Peptides by Applying a Denoising Diffusional Model to mRNA Display Libraries

In vitro directed evolution techniques, such as mRNA display, enable peptide ligand discovery and optimization. However, physical libraries that rely on a genetic code can only search a small fraction of sequence space due to inherent biases in the genetic code and experimental limitations. To address this challenge, denoising diffusion implicit models (DDIMs) are applied to generate novel peptide ligands against B‐cell lymphoma extra‐large (Bcl‐x L ), a key cancer target. Starting with high‐throughput sequencing data from previous selections, a DDIM is trained to produce novel sequences with high affinity binding. Experimental validation confirms that most generated sequences are functionally equivalent to the original library members for Bcl‐x L binding and demonstrated comparable binding kinetics and affinity relative to the wildtype and nearest original neighbors. Importantly, this approach generated rare sequences not easily accessible via mutation and directed evolution. These results indicate that DDIMs can complement and expand directed evolution data, efficiently exploring underrepresented regions of sequence space. This approach provides a broadly applicable framework for accelerating ligand discovery and optimizing molecular properties across diverse targets.

Qi, Pearl [Mork Family Department of Chemical Engi↗