bluuebunny/crossref_metadata_2025 huggingface dataset:
Design, Synthesis and Biological Evaluation of P2-modified Proline Analogues Targeting the HtrA Serine Protease in Chlamydia
Authors: Hwang Jimin , Strange Natalie , Mazraanib Rami , Philips Matthew , Gamble Allan , Huston Wilhelmina , Tyndall Joel
Published: February 2022

High temperature requirement A (HtrA) serine proteases have emerged as a novel class of antibacterial target, which are crucial in protein quality control and are involved in the pathogenesis of a wide array of bacterial infections. Previously, we demonstrated that HtrA in Chlamydia is essential for bacterial survival, replication and virulence. Here, we report a new series of proline (P2)-modified inhibitors of Chlamydia trachomatis HtrA (CtHtrA) developed by proline ring expansion and Cγ-substitutions. The structure-based drug optimization process was guided by molecular modelling and in vitro pharmacological evaluation of inhibitory potency, selectivity and cytotoxicity. Compound 25 from the first-generation 4-substituted proline analogues increased antiCtHtrA potency and selectivity over human neutrophil elastase (HNE) by approximately 6- and 12-fold, respectively, relative to the peptidic lead compound 1. Based on this compound, second-generation substituted proline residues containing 1,2,3-triazole moieties were synthesized by regioselective azide-alkyne click chemistry. Compound 49 demonstrated significantly improved antichlamydial activity in whole cell assays, diminishing the bacterial infectious progeny below the detection limit at the lowest dose tested. Compound 49 resulted in approximately 9- and 22-fold improvement in the inhibitory potency and selectivity relative to 1, respectively. To date, compound 49 is the most potent HtrA inhibitor developed against Chlamydia spp.
Excited States of Crystalline Point Defects with Multireference Density Matrix Embedding Theory
Authors: Mitra Abhishek , Pham Hung , Pandharkar Riddhish , Hermes Matthew , Gagliardi Laura
Published: February 2022

Accurate and affordable methods to characterize the electronic structure of solids are important for targeted materials design. Embedding-based methods provide an appealing balance in the trade-off between cost and accuracy - particularly when studying localized phenomena. Here, we use the density matrix embedding theory (DMET) algorithm to study the electronic excitations in solid-state defects with a restricted open-shell Hartree--Fock (ROHF) bath and multireference impurity solvers, specifically, complete active space self-consistent field (CASSCF) and n-electron valence state second-order perturbation theory (NEVPT2). We apply the method to investigate an oxygen vacancy (OV) on a MgO(100) surface and find absolute deviations within 0.05 eV between DMET using the CASSCF/NEVPT2 solver, denoted as CAS-DMET/NEVPT2-DMET, and the non-embedded CASSCF/NEVPT2 approach. Next, we establish the practicality of DMET by extending it to larger supercells for the OV defect and a neutral silicon-vacancy in diamond where the use of non-embedded CASSCF/NEVPT2 is extremely expensive.
Bioinspired Total Synthesis of (±)-Antroalbocin A enabled by a Photochemical 1,3-Acyl Shift
Authors: Siekmeyer Björn , Lübken Dennis , Bajerke Kevin , Kalesse Markus
Published: February 2022

The first bioinspired and protecting group free total synthesis of the antibacterial sesquiterpenoid antroalbocin A has been achieved in five linear steps from a literature-known intermediate with an overall yield of 6.7%. An intramolecular Robinson annulation gave rapid access to the tricyclic enone as starting material for a photochemical domino process of deconjugation and sigmatropic 1,3 acyl shift. Herein we further describe studies towards the use of photolytic sigmatropic 1,3-acyl shifts in the synthesis of bridged terpenoid building blocks.
Assembling Native Elementary Cellulose Nanofibrils via a Dynamic and Spatially Confined Functionalization
Authors: Beaumont Marco , Tardy Blaise L. , Reyes Guillermo , Koso Tetyana V. , Schaubmayr Elisabeth , Jusner Paul , W. T. King Alistair , DAGASTINE RAYMOND , Potthast Antje , Rojas Orlando J. , Rosenau Thomas
Published: February 2022

Selective surface modification of bio-based fibers affords effective individualization and functionalization into nanomaterials, as shown by the TEMPO-mediated oxidation. However, such route leads to changes of the native surface chemistry, affecting interparticle interactions and limiting the full exploitation of the intrinsic supermaterial properties. Here we introduce a methodology to extract elementary cellulose fibrils by treatment of biomass with N-succinylimidazole, achieving spatially confined (regioselective modification of C6-OH) and dynamic surface functionalization. No polymer degradation or crosslinking nor changes in crystallinity occur under the mild conditions of the process and the modification is fully reversible, which offers a significant opportunity for the reconstitution of the interfaces back to the native states, chemically and structurally. Consequently, access to 3D structuring of native elementary cellulose fibrils is made possible with the same supramolecular features as the bio-synthesized fibers, which is required to unlock the full potential of cellulose as a sustainable building block.
Assembling Native Elementary Cellulose Nanofibrils via a Reversible and Regioselective Surface Functionalization
Authors: Beaumont Marco , Tardy Blaise L. , Reyes Guillermo , Koso Tetyana V. , Schaubmayr Elisabeth , Jusner Paul , W. T. King Alistair , DAGASTINE RAYMOND , Potthast Antje , Rojas Orlando J. , Rosenau Thomas
Published: February 2022

Selective surface modification of bio-based fibers affords effective individualization and functionalization into nanomaterials, as shown by the TEMPO-mediated oxidation. However, such route leads to changes of the native surface chemistry, affecting interparticle interactions and limiting the full exploitation of the intrinsic supermaterial properties. Here we introduce a methodology to extract elementary cellulose fibrils by treatment of biomass with N-succinylimidazole, achieving spatially confined (regioselective modification of C6-OH) and dynamic surface functionalization. No polymer degradation or crosslinking nor changes in crystallinity occur under the mild conditions of the process and the modification is fully reversible, which offers a significant opportunity for the reconstitution of the interfaces back to the native states, chemically and structurally. Consequently, access to 3D structuring of native elementary cellulose fibrils is made possible with the same supramolecular features as the bio-synthesized fibers, which is required to unlock the full potential of cellulose as a sustainable building block.
Trends in bulk compressibility of Mo2-xWxBC solid solutions
Authors: Parry Marcus , Hendry Jackson , Couper Samantha , Oliynyk Anton , Mansouri Tehrani Aria , Brgoch Jakoah , Miyagi Lowell , Sparks Taylor
Published: February 2022

The Mo2-xWxBC system is of interest as a material with high hardness while maintaining moderate ductility. In this work, synchrotron diffraction experiments are performed on Mo2-xWxBC solid solutions, where x = 0, 0.5, and 0.75, upon hydrostatic compression to ~54 GPa, ~55 GPa, and ~60 GPa, respectively. Trends in bulk modulus, K0, are evaluated by fitting collected pressure-volume data with a third-order Birch-Murnaghan equation of state, finding K0 = 333(9) GPa for Mo2BC, K0 = 335(11) GPa for Mo1:5W0:5BC, and K0 = 343(8) GPa for Mo1:25W0:75BC. While K0 demonstrates a slight increase when Mo is substituted by W, calculated zero pressure unit cell volume, V0, exhibits the opposite trend. The decrease in V0 corresponds to an increase in valence electron density, hardness, and K0. Observations corroborate previously reported computational results and will inform future efforts to design sustainable materials with exceptional mechanical properties.
Quantum chemical calculations to trace back reaction paths for the prediction of reactants
Authors: Sumiya Yosuke , Harabuchi Yu , Nagata Yuuya , Maeda Satoshi
Published: February 2022

The long-due development of a computational method for the ab initio prediction of chemical reactants that provide a target compound has been hampered by the combinatorial explosion that occurs when reactions consist of multiple elementary reaction processes. To address this challenge, we have developed a quantum chemical calculation method that can enumerate the reactant candidates from a given target compound by combining an exhaustive automatic reaction path search method with a kinetics method for narrowing down the possibilities. Two conventional name reactions were then assessed by tracing back reaction paths using this new method to determine whether the known reactants could be identified. Our method is expected to be a powerful tool for the prediction of reactants and the discovery of new reactions.
Photo-excited Intramolecular Charge Transfer In Dye Sensitizers : Predictive In-silico Screening for Dye Sensitized Solar Cell Devices
Authors: Chordiya Kalyani , Ali Ehesan , Upadhyay Kahaly Mousumi
Published: February 2022

Efficient photo-induced intramolecular charge transfer (ICT) from donor to acceptor in dye molecules is the functional basis and key property in the working of dye-sensitized solar cell (DSSC). To understand the ICT process in photo-excited dye molecules, we analyse the electronic properties and structural parameters of a chosen set of experimentally synthesized donor-acceptor (D-A) and donor-$\pi$--spacer-acceptor (D-$\pi$-A) type dye molecules in their ground, excited and cationic states. The correlation between structural modification and charge redistribution in different parts of the molecule helps to identify the extent of $\pi$-conjugation and spatial rearrangement of electron density localization along the molecular skeleton. We find that prominent twisting of several groups and resulting molecular bond rearrangements in larger parts of the molecule promotes efficient donor to acceptor ICT, such as in D-A type, ADEKA1 and C275 dyes. Thus based on modest computation of structural and electronic properties of dye molecules in their respective ground, excited and cationic states, we identify the desired structural changes that facilitate tunable intramolecular charge transfer to highlight a simple and direct prescription to screen out probable efficient dye molecules among many samples. Motivated by recent experimental evidence of capturing the structural view of the excited-state charge transfer in molecules, we provide a fresh outlook towards predictive and systematic computational screening and design of dye molecules, complementing parallel experimental approaches in the development of state-of-the-art DSSC.
Catalytic Reduction of Dinitrogen into Ammonia and Hydrazine Using Chromium Complexes Bearing PCP-Type Pincer Ligand
Authors: Ashida Yuya , Egi Akihito , Arashiba Kazuya , Tanaka Hiromasa , Kuriyama Shogo , Yoshizawa Kazunari , Nishibayashi Yoshiaki
Published: February 2022

A series of chromium–halide, –nitride, and –dinitrogen com-plexes bearing a carbene- and phosphine-based PCP-type pin-cer ligand is newly prepared and some of them are found to work as effective catalysts to reduce dinitrogen under atmos-pheric pressure, whereby up to 8.40 equiv of ammonia and 2.46 equiv of hydrazine (13.32 equiv of fixed N atom) are produced based on the chromium atom. To the best of our knowledge, this is the first successful example of chromium-catalyzed conversion of dinitrogen to ammonia and hydrazine under mild reaction conditions.
A General Picture of Cucurbit[8]uril Host-Guest Binding: Recalibrating Bonded Interactions
Authors: Sun Zhaoxi , He Qiaole , Gong Zhihao , Kalhor Payam , Huai Zhe , Liu Zhirong
Published: February 2022

Atomic-level understanding of the dynamical feature of host-guest interactions remains a central challenge in supramolecular chemistry. The remarkable guest binding behavior of the Cucurbiturils family of supramolecular containers makes them promising drug carriers. Among Cucurbit[n]urils, Cucurbit[8]uril (CB8) has intermediate portal size and cavity volume. It can exploit almost all host-guest recognition motifs formed by this host family. In our previous work, an extensive computational investigation of the binding of 7 commonly abused and structurally diverse drugs to the CB8 host was performed and a general dynamical binding picture of CB8-guest interactions was obtained. Further, two widely used fixed-charge models for drug-like molecules were investigated and compared in great detail, aiming at providing guidelines in choosing an appropriate charge scheme in host-guest modelling. Iterative refitting of atomic charges leads to improved binding thermodynamics and the best root-mean-squared deviation from the experimental reference is 2.6 kcal/mol. In this work, we focus on a thorough evaluation of the remaining parts of classical force fields, i.e., the bonded interactions. The widely used general Amber force fields are assessed and refitted to improve the intra-molecular conformational preference and thus the description of inter-molecular host-guest interactions. The interaction pattern and binding thermodynamics show significant dependence on the modelling parameters. The refitted system-specific parameter set improves the consistency of the modelling results and the experimental reference significantly. Finally, combining the previous charge-scheme comparison and the current force-field refitting, we provide general guidelines for the theoretical modelling of host-guest binding.
pH-responsive polymer-based biomacromolecule nanosponges as biodegradable carriers for DOX delivery
Authors: Heidari Nia Marzieh , Ashkar Said , Munguia-Lopez Jose G. , Kinsella Joseph M. , van de Ven Theo G.M.
Published: February 2022

Cellulose is the most abundant renewable biomaterial on earth and beta-cyclodextrin (BCD) is among the most commonly used biocompatible drug encapsulation agents. Combining these bio-organic materials is a very powerful approach to greatly enhance the bioavailability of many drugs. These systems also allow for optimal selective drug release profiles, high biocompatibility, as well as “green nanomedicine” approaches that are eco-friendly in their synthesis and have minimal ecological toxicity. herein, we designed a new type of green and biopolymer-based nanosponge drug carriers which is polymerized by crosslinking beta-cyclodextrin ethylene diamine (βCD-EDA) with bifunctional hairy nanocellulose (BHNC). BHNC contains, besides aldehyde groups, carboxyl groups which can react with amino groups in βCD-EDA. Firstly, the crosslinker βCD-EDA was obtained through a simple nucleophilic substitution reaction between beta-cyclodextrin carbonyl imidazole (βCD-CI) and ethylene diamine (EDA). Secondly, BHNC was functionalized with the crosslinker βCD-EDA through a facile nucleophilic substitution crosslinking reaction of the BHNC activated carboxyl groups by the amines of βCD-EDA. We refer to the polymerized highly crosslinked BHNC-βCD-EDA network as BBE. Various ratios of βCD-EDA and BHNC were polymerized with the help of DMTMM as an activator, which resulted in different morphological shapes of BBE, and thus in different release profiles and pH-responsiveness. Unlike other polymer-based βCDs and nanosponges, these new types of crosslinked polymer were prepared in a green and safe solvent (water) and with very short reaction times and at low temperatures. Finally, the BBE polymers were tested as biocompatible nanocarriers for controllable doxorubicin (DOX) delivery. These hyper crosslinked polymers show a high capacity for loading DOX with extended drug release. Furthermore, breast cancer cell cultures show lower cell viability when DOX was loaded in various BBEs than control samples or DOX alone, indicating that our DOX-BBE drug delivery systems are better anticancer agents than DOX alone.
A Reliable and Sustainable Multicomponent Access to Protein Degraders
Authors: Bhela Irene Preet , Ranza Alice , Serafini Marta , PIRALI Tracey
Published: February 2022

The use of small molecules to induce targeted protein degradation is increasingly growing in the drug discovery landscape and protein degraders have progressed rapidly through the pipelines. Despite the advances made so far, their synthesis still represents a significant burden and new approaches are urgently demanded. Herein, we report an unprecedented platform that leverages the modular nature of both multicomponent reactions and degraders to enable the preparation of highly decorated PROTACs and hydrophobic tag-mediated degraders. Compared to the existing methods, our approach offers a versatile and cost-effective means to access libraries of protein degraders and increase the chance of identifying successful clinical candidates.
Bayesian optimization of nanoporous materials
Authors: Deshwal Aryan , Simon Cory , Doppa Janardhan Rao
Published: February 2022

Given a gas storage or separation task, we wish to search a library of nanoporous materials (NPMs) for the one with the optimal adsorption property. The high cost of measuring the adsorption property of an NPM, whether in the lab or a simulation, precludes exhaustive search. We explain, demonstrate, and advocate Bayesian optimization (BO) to find the optimal NPM in a library of NPMs using the fewest experiments. The two ingredients of BO are a surrogate model and an acquisition function. The surrogate model is a probabilistic model reflecting our beliefs about the NPM-structure--property relationship based on observations from past experiments. The acquisition function uses the surrogate model to score each NPM according to the utility of picking it for the next experiment, while balancing exploitation and exploration. We demonstrate BO by searching a database of covalent organic frameworks (COFs) for the COF with the highest simulated methane deliverable capacity.
Amphotericin B Assembles into Seven-Molecule Ion Channels: An NMR and Molecular Dynamics Study
Authors: Umegawa Yuichi , Yamamoto Tomoya , Dixit Mayank , Funahashi Kosuke , Seo Sangjae , Nakagawa Yasuo , Suzuki Taiga , Matsuoka Shigeru , Tsuchikawa Hiroshi , Hanashima Shinya , Oishi Tohru , Matsumori Nobuaki , Shinoda Wataru , Murata Michio
Published: February 2022

Amphotericin B, an antifungal drug with a long history of use, forms fungicidal ion-permeable channels across cell membranes. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we experimentally elucidated the three-dimensional structure of the molecular assemblies formed by this drug in membranes in the presence of fungal sterol, ergosterol. A stable assembly consisting of seven drug molecules was observed to form an ion conductive channel. The structure is somewhat similar to the upper half of the barrel-stave model proposed in the 1970s but substantially different in the number of molecules and in their arrangement. The high-resolution structure explains many previous findings, including structure-activity relationships of the drug, which will be useful for improving drug efficacy and reducing adverse effects.
Amphotericin B Assembles into Seven-Molecule Ion Channels in Membrane Domain
Authors: Umegawa Yuichi , Yamamoto Tomoya , Dixit Mayank , Funahashi Kosuke , Seo Sangjae , Nakagawa Yasuo , Suzuki Taiga , Matsuoka Shigeru , Tsuchikawa Hiroshi , Hanashima Shinya , Oishi Tohru , Matsumori Nobuaki , Shinoda Wataru , Murata Michio
Published: February 2022

Amphotericin B, a long-used antifungal drug, forms fungicidal ion-permeable channels across cell membranes. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we experimentally elucidated the three-dimensional structure of the molecular assemblies formed by this drug in membranes in the presence of the fungal sterol, ergosterol. A stable assembly of seven drug molecules was observed to form an ion conductive channel. The structure somewhat resembled the upper half of the barrel-stave model proposed in the 1970s but different substantially in the number of molecules and their arrangement. Based on the structure obtained, the aggregation of the channel assemblies in membranes was investigated and a mechanism was proposed in which complexation with ergosterol stabilizes the drug’s assemblies, leading to their aggregation, and in turn enhancing channel activity. The high-resolution structure is consistent with many previous findings, including structure-activity relationships of the drug, and the channel aggregation provides a more reasonable explanation for the selective toxicity of this drug to fungi.
Questioning the orbital picture of magnetic spin coupling: a real space alternative
Authors: Martín Pendás Ángel , Francisco Evelio
Published: February 2022

The prevailing magnetic spin coupling paradigm is based on a one-electron picture, thus being orbital dependent and unsatisfactory from a physical point of view. We examine it under a truly invariant real space perspective, focusing on the role of electron delocalization. We show that this view, compatible with orbital thinking, overcomes its limitations. By examining simple model systems we show that it is electron delocalization that drives any singlet-triplet gap, and that delocalization and ionic mixing are two sides of the same reality. It is in the end delocalization, fostered or hindered by the specific structure of a system, that lies behind its preferred magnetic coupling mode. In the case of superexchange-mediated coupling through atomic bridges, we also point out the non-essential role of the bridge's electrons in setting up singlet-triplet preferences. We show that the use of real space thinking allows for tuning singlet-triplet gaps using knobs that are not easily grasped from the orbital standpoing, opening new avenues in the design and control of molecular magnets.
Protective effect of starch-stabilized selenium nanoparticles against the hepato-renal melamine-induced toxicity in male albino rats
Authors: Ahmed Zainab Sabry Othman , Galal Mona K. , Drweesh Elsayed A. , Abou-El-Sherbini Khaled S. , Elzahany Eman A.M. , Elnagar Mohamed , Yasin Noha A. E.
Published: February 2022

Melamine and its analogues are illegally added to falsify the content of protein in food products. The elevated concentrations of these compounds cause harmful effects in humans and animals. In this contribution, the potential ability of synthesized starch-stabilized selenium nanoparticles (Se-NPs@starch) towards inhibiting the toxicity of melamine on the liver and kidneys has been systematically investigated. The Se-NPs@starch were characterized by XPS analysis, EDS mapping analysis, TEM, and FT-IR. Starch plays a crucial role in the stabilization and dispersion of Se NPs, as noticed from the TEM and EDS investigations. Furthermore, the atomic ratio of Se distribution over starch surface is approximately 1.67%. To evaluate the activity of Se-NPs@starch, this study was conducted on four groups of adult male rats. Group I (the control group), group II received Se-NPs@starch, group III received melamine, whereas group IV received melamine and Se-NPs@starch. The results reveal a significant alteration in the histoarchitecture of both hepatic and renal tissues induced by melamine. While melamine induces severe toxic effects on the hepatic and renal tissues, the administration of Se-NPs@starch results in remarkable protection of rats against melamine-induced toxicity. Collectively, the affordable starch-stabilized Se-NPs have a potent biological activity, making them auspicious candidates for biomedical applications.
The modelling of multi-resonant thermally activated delayed fluorescence emitters – properly accounting for electron correlation is key!
Authors: Hall David , Sancho Juan Carlos , Pershin Anton , Beljonne David , Zysman-Colman Eli , Olivier Yoann
Published: February 2022

With the surge of interest in multi-resonant thermally activated delayed fluorescent (MR-TADF) materials it is important that there exist computational methods to accurately model their excited states. Here, building on our previous work, we demonstrate how the Spin-Component Scaling second-order approximate Coupled-Cluster (SCS-CC2), a wavefunction-based method, is robust at predicting the ΔEST (i.e., the energy difference between the lowest singlet and triplet excited states) of a large number of MR-TADF materials, with a mean average deviation (MAD) of 0.04 eV compared to experimental data. Time-Dependent Density Functional Theory calculations with the most common DFT functionals as well as the consideration of the Tamm-Dancoff approximation (TDA) consistently predict a much larger ΔEST owing to the absence of an explicit account of double (or higher order) excitations. This contribution is key in order to describe more precisely the Coulomb correlation that results in a stabilization of the S1 state. We also employed SCS-CC2 to evaluate donor-acceptor systems that contain a MR-TADF moiety acting as the acceptor and show that the broad emission observed for some of these compounds arises from the solvent-promoted stabilization of a higher-lying charge transfer (CT) singlet state (S2). This work highlights the importance of using wavefunction methods in relation MR-TADF emitter design and associated photophysics.
Using wide biological pores to cap and contain the COVID-19 spike protein
Authors: Sampath G
Published: February 2022

Geometric analysis shows that the spike (S) protein in the COVID-19 virus (SARS-Cov-2) can fully or partially enter into the channel of a wide biological pore like perforin (PFN) or streptolysin (SLO) when the latter is anchored in a bilayer lipid membrane. The PFN channel is a β barrel formed from multiple monomers, for example a ~14 nm diameter channel is formed from 22 monomers. Coincidentally the wide canopy of S (which has three identical chains) has an enclosing diameter of ~14 nm. While inside the channel peripheral residues in the canopy may bind with residues on the pore side of the barrel. If there are no adverse cross-reactions this would effectively prevent S from interacting with a target cell. Calculations with data obtained from PDB and other sources show that there are ~12 peripheral residue triples in S within a circle of diameter ~14 nm that can potentially bind with 22 exposed residues in each barrel monomer. The revised Miyazawa-Jernighan matrix is used to calculate the binding energy of canopy-PFN barrel residue pairs. The results show a large number of binding pairs over distances of up to 38 Å into the pore. This geometric view of capture and containment points to the possibility of using biological pores to neutralize SARS-Cov-2 in its many variant forms. Some necessary conditions that must be satisfied for such neutralization to occur are noted.
Tunable and Recyclable Polyesters from CO2 and Butadiene
Authors: Rapagnani Rachel , Dunscomb Rachel , Fresh Alexandra , Tonks Ian
Published: February 2022

Carbon dioxide is inexpensive and abundant, and its prevalence as waste makes it attractive as a sustainable chemical feedstock. Although there are examples of copolymerizations of CO2 with high-energy monomers, the direct copolymerization of CO2 with olefins has not been reported. Herein, an alternate route to tunable, recyclable polyesters derived from CO2 and butadiene via an intermediary lactone, 3-ethyl-6-vinyltetrahydro-2H-pyran-2-one, is described. Catalytic ring-opening polymerization of the lactone by 1,5,7-triazabicyclo[4.4.0]dec-5-ene yields polyesters with molar masses up to 13.6 kg/mol and pendent vinyl sidechains that can undergo post-polymerization functionalization. The polymer has a low ceiling temperature of 138 ºC, allowing for facile chemical recycling. These results mark the first example of a well-defined polyester derived solely from CO2 and olefins, expanding access to new feedstocks that were once considered unfeasible.
Computational investigation on natural quinazoline alkaloids as potential inhibitors of the main protease (Mpro) of SARS_CoV_2
Authors: Banerjee Deb Ranjan , Jana Abhisek , Roy Tarun , Layek Sarbajit , Ghosal Subhash
Published: February 2022

Drug discovery is still behind in the race compared to vaccine discovery in fighting COVID-19. Recently, a few alkaloids from a traditional Indian medicinal plant, Vasaka (Justicia adhatoda), have been linked computationally to the main protease (Mpro) of SARS_CoV_2. To expand the knowledge and for further investigation, we have selected 41 quinazoline alkaloids from two natural product databases to create an adequate library and performed detailed computational studies against the main protease (Mpro) of SARS_CoV_2. The screening of the library was carried out through blending the rigid docking and pharmacokinetic analysis that resulted in nine alkaloids as initial leads against Mpro. These nine alkaloids were further subjected to advance flexible docking using first reference famotidine for the analysis of structure-based interactions. For further selection, a second screening was carried out based on binding energies and interaction profiles that yielded three alkaloids namely CNP0416047, 3-hydroxy anisotine and anisotine as hits. The stereo-electronic features of hit alkaloids were further investigated through additional structure-based E-pharmacophore mapping against a second reference, known X77 ligand. Additionally, the reactivity of hit alkaloids at the binding site of the protein was estimated by measuring the electron distribution on the frontier molecular orbitals and HOMO-LUMO band energies. Finally, the stabilities of complexes between hit alkaloids with the protein were accessed extensively using robust molecular dynamics simulation through RMSD, RMSF, Rg, and MM-PBSA calculation. Thus, this study identifies three natural quinazoline alkaloids as potential inhibitors of MPro through extensive computational analysis.
Improvement of the Gaussian Electrostatic Model by Separate Fitting of Coulomb and Exchange-Repulsion Densities and Implementation of a new Dispersion term
Authors: Naseem-Khan Sehr , Piquemal Jean-Philip , Cisneros G. Andrés
Published: February 2022

The description of each separable contribution of the intermolecular interaction is a useful approach to develop polarizable force fields (polFF). The Gaussian Electrostatic Model (GEM) is based on this approach, coupled with the use of density fitting techniques. In this work, we present the implementation and testing of two improvements of GEM: the Coulomb and Exchange-Repulsion energies are now computed with separate frozen molecular densities, and a new dispersion formulation inspired by the SIBFA polFF, which has been implemented to describe the dispersion and charge–transfer interactions. Thanks to the combination of GEM characteristics and these new features, we demonstrate a better agreement of the computed structural and condensed properties for water with experimental results, as well as binding energies in the gas phase with the ab initio reference compared with the previous GEM* potential. This work provides further improvements to GEM and the items that remain to be improved, and the importance of the accurate reproduction for each separate contribution.
Computational Design of Double-Layer Cathode Coatings in All-Solid-State Batteries
Authors: Wang Chuhong , Aoyagi Koutarou , Mueller Tim
Published: February 2022

All-solid-state lithium-ion batteries have great potential for improved energy and power density compared to conventional lithium-ion batteries. With extensive research efforts devoted to the development of inorganic superionic conductors, lithium thiophosphates stand out due to their high ionic conductivity and room‐temperature processability. However battery rate performance still suffers from increased impedance attributed to the interfacial reactions between thiophosphate electrolyte and oxide electrodes. Stabilizing the interfaces with a protective coating layer has been proposed as a solution to the interfacial problem, but it is rare for a material to simultaneously exhibit fast ionic conductivity and chemical stability at battery interfaces. Here, we propose a double-layer coating design comprising a sulfide-based layer adjacent to the thiophosphate electrolyte accompanied by a layer that is stable against the oxide cathode. Based on a high-throughput thermodynamic stability screen and active learning molecular dynamics simulations, we identify several sulfide + halide couples that potentially outperform the known coating materials in interfacial stability as well as ionic conductivity. Several halides we identify have been recently identified as novel solid electrolyte candidates. We highlight the integration of room-temperature fast ionic conductors Li5B7S13 (137 mS cm−1), Li7Y7Zr9S32 (6.5 mS cm−1), and Li(TiS2)2 (0.0008 mS cm−1) which potentially reduces interfacial reactivity with minor loss of charge transfer rate through the thiophosphate electrolyte.
Combining genetically engineered oxidase with hydrogen bonded organic framework (HOF) for highly efficient biocomposites.
Authors: Wied Peter , Carraro Francesco , Bolivar Juan , Doonan Christian , Falcaro Paolo , Nidetzky Bernd
Published: February 2022

Hydrogen bonded organic frameworks (HOFs) with enzymes incorporated during their bottom-up synthesis represent functional biocomposites with promising applications in catalysis and sensing. High enzyme loading while preserving high specific activity is fundamental for development, but to combine these biospecific features with a porous carrier is an unmet challenge. Here, we explored synthetic incorporation of D-amino acid oxidase (DAAO) with metal-free tetraamidine/tetracarboxylate-based BioHOF-1. Comparison of different DAAO forms in BioHOF-1 incorporation revealed that N-terminal enzyme fusion with the positively charged module Zbasic2 (Z-DAAO) promotes the loading (2.5-fold; ~500 mg g-1) and strongly boosts the activity (6.5-fold). To benchmark the HOF composite with metal-organic framework (MOF) composites, Z-DAAO was immobilized into the zeolitic imidazolate framework-8 (ZIF-8), the relatively more hydrophilic analogue metal azolate framework-7 (MAF-7). While sensitivity to the framework environment limited the activity of DAAO@MAF-7 (3.2 U mg-1) and DAAO@ZIF-8 (≤ 0.5 U mg-1), the activity of DAAO@BioHOF-1 was comparable (~45%) to that of soluble DAAO (50.1 U mg-1) and independent of the enzyme loading (100 – 500 mg g-1). The DAAO@BioHOF-1 composites showed superior activity with respect to every reported carrier for the same enzyme and excellent stability during solid catalyst recycling. Collectively, our results show that the fusion of the enzyme with a positively charged protein module enables the synthesis of highly active HOF biocomposites suggesting the use of genetic engineering for the preparation of biohybrid systems with unprecedented properties.
A scalable galvanic approach to microswimmer synthesis
Authors: Bailey Maximilian , Reichholf Nico , Flechsig Anne , Grillo Fabio , Isa Lucio
Published: February 2022

Microswimmers are small particles capable of converting available energy sources into propulsion owing to their compositional asymmetry and are promising for applications ranging from targeted delivery to enhanced mixing at the microscale. However, current fabrication techniques demonstrate limited scalability and/or rely on the excessive use of expensive precursor materials. Here, a scalable Pickering-wax emulsion technique is combined with galvanic electrochemistry, to grow platinum films from copper nanoparticles asymmetrically seeded onto SiO\textsubscript{2} microparticle supports. In this manner, large quantities of Pt-SiO\textsubscript{2} Janus microswimmers are obtained. Utilising copper as a templating material not only reduces synthesis time, material costs, and toxic waste, but also facilitates the further extension of this methodology to a range of functional materials. This electrochemical approach builds upon previous attempts to overcome the current limitations in microswimmer synthesis and offers exciting opportunities for their future development.
Carbene Character in a Series of Neutral PCcarbeneP Cobalt(I) Complexes – Radical Carbenes Versus Nucleophilic Carbenes
Authors: Clapson Marissa , Kirkland Justin , Piers Warren , Ess Daniel , Gelfand Benjamin , Lin Jian-Bin
Published: February 2022

Cobalt(I) complexes supported by a series of PCcarbeneP pincer ligands of varying donicity, differing in the aryl group linking the phosphine arms with the anchoring carbon donor, are described. Addition of the proligands to cobalt bromide results in the formation of a series of cobalt(II) tetrahedral complexes, Ln-1, which serve as excellent precur-sors to the corresponding PCalkylP and PCcarbeneP complexes. Square planar cobalt PCcarbeneP complexes, L2R-3-X (X = Cl, Br), are readily synthesized by addition of a bulky aryloxide radical to the corresponding PCalkylP complex, L1-2-Br or via addition of L2R to ClCo(PPh3)3 in the presence of trityl radical or by addition of NaHBEt3 and trityl radical to iso-lated L2R-1. For the L2NMe2 PCcarbeneP complexes, salt metathesis reactions with either CsOH·H2O, LiCH2TMS, or LiNH2 result in the corresponding hydroxo, alkyl, and amine complexes, L2NMe2-3-R (R = OH, CH2TMS, NH2). Reaction of L2NMe2-3-OH with benzoic acid affords the 2-O2CPh derivative The nature of the carbene bond in either ligand plat-form as well as the effects of the X-type capping ligand on the Co=C bond are explored computationally and show that triplet structures are relatively more stable in for the less electron donating ligand L1 while singlet Co(I) carbenes dominate for the more electron rich L2 derivatives. For L2NMe2 complexes, the effect of the trans ligand X was also probed. Pi donors imbue the carbene with singlet character while the strongly  donating alkyl derivative exhibits significant triplet character.
Phase Stability of the Tin Monochalcogenides SnS and SnSe: A Quasi-Harmonic Lattice-Dynamics Study
Authors: Pallikara Ioanna , Skelton Jonathan
Published: February 2022

The tin monochalcogenides SnS and SnSe adopt four different crystal structures, viz. orthorhombic Pnma and Cmcm and cubic rocksalt and π-cubic (P213) phases, each of which has optimal properties for a range of potential applications. This rich phase space makes it challenging to identify the conditions under which the different phases are obtained. We have performed first-principles quasi-harmonic lattice-dynamics calculations to assess the relative stabilities of the four phases of SnS and SnSe. We investigate dynamical stability through the presence or absence of imaginary modes in the phonon dispersion curves, and we compute Helmholtz and Gibbs free energies to evaluate the thermodynamic stability. We also consider applied pressures from 0-15 GPa to obtain temperature-pressure phase diagrams. Finally, the relationships between the different crystal phases are investigated by explicitly mapping the potential-energy surfaces along the imaginary phonon modes and by using the climbing-image nudged elastic-band method.
Modelling the structure and interactions of intrinsically disordered proteins with multiple-replica, metadynamics-based sampling methods and force-field combinations
Authors: Li Lunna , Casalini Tommaso , Arosio Paolo , Salvalaglio Matteo
Published: February 2022

Intrinsically disordered proteins (IDPs) play a key role in many biological processes, including the formation of biomolecular condensates within cells. A detailed characterization of their configurational ensemble and structure-function paradigm is crucial for understanding their biological activity and for exploiting them as building blocks in material sciences. In this work, we incorporate bias-exchange metadynamics and parallel-tempering well-tempered metadynamics with CHARMM36m and CHARMM22* to explore the structural and thermodynamic characteristics of a short archetypal disordered sequence derived from a DEAD-box protein. The conformational landscapes emerging from our simulations are largely congruent across methods and forcefields. Nevertheless, differences in fine details emerge from varying forcefield/sampling method combinations. For this protein, our analysis identifies features that help to explain the low propensity of this sequence to undergo self-association in vitro, which can be common to all force-field/sampling method combinations. Overall, our work demonstrates the importance of using multiple force-field/enhanced sampling method combinations for accurate structural and thermodynamic information in the study of general disordered proteins.
Expedient Synthesis of Bis(imidazolium) Dichloride Salts and Bis(NHC) Complexes from Imidazoles using DMSO as a Key Polar Additive
Authors: Penn Kyle , Anders Evan , Lindsay Vincent
Published: February 2022

A general approach for the synthesis of bis(imidazolium) dichloride salts from imidazoles and dichloroalkanes is reported. Typical limitations of this reaction for the formation of methylene-bridged derivatives are addressed herein through the use of an excess CH2Cl2 in the presence of DMSO as a polar cosolvent, significantly improving conversion rates presumably via stabilization of the initial SN2 transition state. The method was also shown to be applicable to the formation of bis(pyridinium) dichloride salts from pyridine derivatives, and to the direct synthesis of metal-bis(NHC) complexes from imidazoles.
Electrostatic vs. Inductive Effects in Phosphine Ligand Donor Properties, Reactivity, and Catalysis
Authors: Kelty Margaret L. , McNeece Andrew J. , Filatov Alexander S. , Anderson John
Published: February 2022

The use of charged groups to leverage electrostatics in molecular systems is a promising strategy to tune reactivity. However, disentangling the relative influences of inductive (through-bond) and electrostatic (through-space) contributions from charged groups is a long-standing challenge. To quantify the interplay of these effects we have synthesized and analyzed the anionic phosphine, Ph2PCH2BF3−, its selenide, and its transition metal complexes. Solvent-dependent changes in donor strength consistent with Coulomb’s law support a dominant electrostatic contribution to donor strength, while computations highlight the impact of charge position and orientation. Finally, inclusion of the anion also greatly accelerates C–F oxidative addition reactivity in Ni complexes, allowing for rapid catalytic C–F borylation of fluoroarenes. These results show that covalently bound charged functionalities can exert a major electrostatic influence under common solution phase reaction conditions.
Evidence of Gas-phase Pyranose-to-furanose Isomerization in Protonated Peptidoglycans
Authors: Guan Shanshan , Bythell Benjamin
Published: February 2022

Peptidoglycans are diverse co- and post-translational modifications of key importance in myriad biological processes. Mass spectrometry is employed to infer their biomolecular sequences and stereochemisties, but little is known about the critical gas-phase dissociation processes involved. Here, using tandem mass spectrometry (MS/MS and MSn), isotopic labelling and high-level simulations, we identify and characterize a facile isomerization reaction that produces furanose N-acetylated ions. This reaction occurs for both O- and N-linked peptidoglycans irrespective of glycosidic linkage stereochemistry (α/β). Dissociation of the glycosidic and other bonds thus occur from the furanose isomer critically altering the reaction feasibility and product ion structures.
Carbon-Binder Migration: A Three-Dimensional Evaporation Model for Lithium Ion Batteries
Authors: Lombardo Teo , Ngandjong Alain , Belhcen Amal , Chouchane Mehdi , Shodiev Abbos , Arcelus Oier , Franco Alejandro A.
Published: February 2022

Li-ion battery electrodes manufacturing is raising broad interest from both experimental and computational perspectives, due to its impact on the cost, mechanical and electrochemical properties of the final electrodes and cells. Among the different manufacturing steps, solvent evaporation can trigger heterogeneities along the electrode mesostructure through additives migration, which were found to affect significantly the final electrodes’ properties. In this work, we present the first physics-based three-dimensional model able to mimic the additives migration occurring along the drying step, unlocking the generation of three-dimensional heterogeneous electrode mesostructures. We analyzed the effect of drying rate on the final electrode mesostructures, the dynamics of additives migration and how the developed heterogeneities affect the following manufacturing step, i.e. electrodes’ compression. The results are in agreements with previous experimental findings and indicates trends not disclosed yet. Lastly, the implementation of complex drying procedures (three-stage drying) was tested and compared to its experimental counterpart.
Gelation and Yielding Behavior of Polymer-Nanoparticle Hydrogels
Authors: Grosskopf Abigail , Saouaf Olivia , Lopez Hernandez Hector , Appel Eric
Published: February 2022

Polymer-Nanoparticle hydrogels are a unique class of self-assembled, shear-thinning, yield-stress fluids which haved demonstrated potential utility in many impactful applications. Here we present a thorough analysis of the gelation and yielding behavior of these materials with respect to the polymer and nanoparticle component stoichiometry. Through comprehensive rheological and diffusion studies, we reveal insights into the structural dynamics of the polymer nanoparticle network which identify that stoichiometry plays a key role in gelation and yielding, ultimately enabling the development of hydrogel formulations with unique shear-thinning and yield-stress behaviors. Access to these materials opens new doors for interesting applications in a variety of fields including tissue engineering, drug delivery, and controlled solution viscosity.
Hardness of new boron-rich chalcogenides B12S and B12Se
Authors: Solozhenko Vladimir
Published: February 2022

Hardness of bulk polycrystalline boron-rich chalcogenides, rhombohedral B12S and B12Se, has been predicted using contemporary theoretical models and experimentally studied by microindentation. Both chalcogenides exhibit Vickers hardness of about 33 GPa exceeding that of boron carbide and hence belong to a family of (super)hard phases.
Accounting for Dispersion Effects in DFT Framework of Electrocatalysis: A Case Study of Solvent Mediated Oxygen Reduction Reaction
Authors: S. Nair Akhil , Pathak Biswarup
Published: February 2022

Density functional theory (DFT) is a pivotal tool in the field of computational electrocatalysis. Dispersion effects, which are not incorporated in the regular DFT framework, play a significant role in improving the accuracy of DFT-based catalytic simulations. We perform a calibration study for addressing the effect of different dispersion corrected DFT methods in determining the electrocatalytic properties by conducting a case study of oxygen reduction reaction (ORR). The distinct trends of these methods towards determining the structural, energetic, and electronic properties of catalysis are scrutinized. By systematically incorporating an upgraded solvation model, the importance of the inclusion of dispersion effects for the accurate prediction of chemical and physical properties governing the catalytic activity is illustrated. The combined thermodynamic and kinetic analysis predicts a uniform ORR activity trend, with semi-empirical dispersion corrected DFT methods emerging as optimal choices with comparable or higher accuracy than advanced van der Waal’s methods.