bluuebunny/crossref_metadata_2025 huggingface dataset:
Donor-Acceptor Polymer Networks from Triarylborane and Thiophene Building Blocks for Photocatalytic Hydrogen Evolution from Aqueous Solution
Authors: Trunk Matthias , Li Guiping , Burmeister David , Obermeier Martin , Bonkano Boubacar Tanda , Schwalbe Matthias , Bojdys Michael
Published: February 2022

Photocatalytic water-splitting provides a carbon-neutral alternative to energy-intensive electrolysis to store solar energy in the form of hydrogen. Microporous polymer networks are an intriguing platform for the design of increasingly more performant photocatalysts due to their chemical modularity and band-gap tuning potential. Their efficacy depends on the efficient separation of photoexcited electron-hole pairs. Conventionally, this is achieved by deposition of expensive platinum as co-catalyst. More recently, however, it was recognized that efficiency of polymer photocatalysts can be improved by incorporation of donor-acceptor motifs into their backbones. While electron donors are plentiful, there is little variety in electron acceptor motifs. We synthesised a series of microporous donor-acceptor networks that contain electron-deficient triarylborane moieties with the unique electronic properties of tricoordinate boron as an electron acceptor. Under sacrificial conditions, these polymers feature hydrogen evolution rates of up to 113.9 mmol h-1 g-1 that decrease only marginally under omission of platinum co-catalyst. This work outlines a clear synthetic strategy towards truly noble-metal-free photocatalysts.
Potential of phenolic compounds and their gut microbiota-derived metabolites to reduce microbial TMA formation: Application of an in vitro fermentation high throughput screening model
Authors: Iglesias-Carres Lisard , Krueger Emily , Herring Jacob , Tessem Jeffery , Neilson Andrew
Published: February 2022

Trimethylamine N-oxide (TMAO) is a pro-atherosclerotic product of dietary choline metabolism generated by a microbiome-host axis. The first step in this pathway is enzymatic metabolism of choline to trimethylamine (TMA) by the gut microbiota. This reaction could be targeted to reduce atherosclerosis risk. We aimed to evaluate potential inhibitory effects of select dietary phenolics and their relevant gut microbial metabolites on TMA production via a human ex vivo-in vitro fermentation model. Various phenolics inhibited choline use and TMA production, especially larger compounds or their larger metabolites, without altering cell respiration or cell growth. However, inhibitory effects decreased at late fermentation times, which suggest that these compounds delay choline metabolism rather than completely inhibiting TMA formation. Overall, caffeic acid, catechin and epicatechin were the most effective non-cytotoxic inhibitors of choline use and TMA production. Thus, these compounds are proposed as lead bioactives to test in vivo.
An improved route to osmium(IV) tetraaryl complexes
Authors: Parr Joseph , Olivar Clarissa , Saal Thomas , Haiges Ralf , Inkpen Michael
Published: February 2022

Investigations into the reactivity, properties, and applications of osmium(IV) tetraaryl complexes have been hampered by their low yielding syntheses from volatile and toxic OsO4 (typically ≤34%). Here we show that air-stable M(aryl)4 compounds (M = Os, Ru; aryl = 2-tolyl, 2,5-xylyl) can be prepared in improved yields (≤73%) starting from new, less hazardous (Oct4N)2[MX6] precursors (M = Os, Ru; X = Cl, Br). This approach also facilitates the preparation of Os(mesityl)4 (Os3), a complex comprising bulky 2,6-methyl substituted aryl ligands, for the first time (5% yield). We evaluate the X-ray crystal structures of Os(2,5-xylyl)4 (Os2) and Os3, employing a "tetrahedricity" metric that shows Os3 has a particularly distorted tetrahedral geometry compared to other Ru(aryl)4 and Os(aryl)4 materials. The 1H NMR spectrum of Os3 exhibits significantly broadened features at 298 K that split into distinct resonances at low temperatures, indicative of restricted rotation of the mesityl ligands around the Os-aryl 𝜎-bond. Solution cyclic voltammograms of Os(aryl)4 reveal that the potentials of their known reversible redox features can be fine-tuned by varying the number of ligand methyl substituents, and that Os3 exhibits an additional 1+/2+ redox event not previously observed in this class of compounds. This work aims to help advance the potential application of these relatively underexplored organometallic complexes in established and emerging areas of molecular materials science, such as extended molecular frameworks and self-assembled monolayers, where analogous tetraphenylmethane and silane species (M = C, Si) have been frequently targeted.
Highly regioselective surface acetylation of cellulose and shaped cellulose constructs in the gas-phase
Authors: Koso Tetyana , Beaumont Marco , Tardy Blaise , Rico del Cerro Daniel , Eyley Samuel , Thielemans Wim , Rojas Orlando , Kilpeläinen Ilkka , King Alistair
Published: February 2022

Gas-phase acylation of cellulose is an attractive method for modifying the surface properties of cellulosics. However, little is known concerning the regioselectivity of the chemistry, in terms of which cellulose positions are preferentially acylated and if acylation can be restricted to the surface, preserving crystallinities/morphologies. Consequently, we reexplore simple gas-phase acetylation of modern-day cellulosic building blocks – cellulose nanocrystals, pulps, regenerated fibre and aerogels. The gas-phase acetylation is shown to be highly regioselective for the C6-OH, is further supported with computational modelling. This contrasts with liquid-state acetylation, highlighting that the gas-phase chemistry is much more controllable, yet with similar kinetics to the uncatalyzed liquid-phase reactions. Furthermore, this method preserves both the native crystalline structure of cellulose and the supramolecular morphologies of even delicate cellulosic constructs (aerogel exhibiting retention of chiral cholesteric liquid crystalline phases). Therefore, we are convinced that this methodology will lead to more rapid adoption of precisely tailored and cellulosic materials
An S-Shaped Double Helicene Showing both Multi-Resonance Thermally Activated Delayed Fluorescence and Circularly Polarized Luminescence
Authors: Dos Santos John , Sun Dianming , Moreno-Naranjo Juan , Hall David , Zinna Francesco , Ryan Seán , Shi Wenda , Matulaitis Tomas , Cordes David , Slawin Alexandra , Beljonne David , Warriner Stuart , Olivier Yoann , Zysman-Colman Eli , Fuchter Matthew
Published: February 2022

We present the first example of a multi-resonant thermally activated delayed fluorescent (MR-TADF) helicene, Hel-DiDiKTa. This S-shaped double helicene exhibits sky-blue emission, a singlet-triplet energy gap, EST, of 0.15 eV and narrow emission at a peak maximum of 473 nm with a full-width at half-maximum of 44 nm in toluene. The MR-TADF character is confirmed by the small degree of positive solvatochromism and temperature-dependent increase in intensity of the delayed emission. The chiroptical properties of the separated enantiomers are similar to other large helicenes with comparable dissymmetry values, but with the added benefit of MR-TADF. Thus, this study further strengthens the burgeoning area of chiral TADF emitters for use in cutting-edge optoelectronic and photocatalytic molecules and materials.
Molecular scale chemical imaging of the orientation of an on-surface coordination complex by tip-enhanced Raman spectroscopy
Authors: Cai Zhen-Feng , Zheng Li-Qing , Zhang Yao , Zenobi Renato
Published: February 2022

Metal-organic coordination structures at interfaces play an essential role in many biological and chemical systems. Understanding the molecular specificity, orientation and spatial distribution of the coordination complexes at the nanometer scale is of great im-portance for effective molecular engineering of nanostructures and fabrication of functional devices with controllable properties. However, fundamental properties of such coordination systems are still rarely studied directly. In this work, we present a spectro-scopic approach on the basis of tip-enhanced Raman spectroscopy (TERS) to investigate a cobalt(II) tetraphenyl-porphyrine (CoTPP) coordination species on the scale of a single molecule under ambient conditions. Coordination species anchored on gold surfaces modified with pyridine thiol self-assembled monolayers can be spectroscopically distinguished and mapped with ca. 2 nm resolution. In addition, in combination with density functional theory simulations, the adsorption configuration and molecular ori-entation of the coordination complexes are also revealed using TERS imaging.
Quantum Mechanics Enables "Freedom of Design" in Molecular Property Space
Authors: Medrano Sandonas Leonardo , Hoja Johannes , Ernst Brian G. , Vazquez-Mayagoitia Alvaro , DiStasio Jr. Robert A. , Tkatchenko Alexandre
Published: February 2022

Rational design of molecules with targeted properties requires understanding quantum-mechanical (QM) structure-property/property-property relationships (SPR/PPR) across chemical compound space. We analyze these relationships using the QM7-X dataset---which includes multiple QM properties for ~4.2 M equilibrium and non-equilibrium structures of small (primarily organic) molecules. Instead of providing simple SPR/PPR that strictly follow physicochemical intuition, our analysis uncovers substantial flexibility in molecular property space (MPS) when searching for a single molecule with a desired pair of QM properties or distinct molecules with a targeted set of QM properties. As proof-of-concept, we used Pareto multi-property optimization to search for the most promising (i.e., highly polarizable and electrically stable) molecules for polymeric battery materials; without prior knowledge of this complex manifold of MPS, Pareto front analysis reflected this intrinsic flexibility and identified small directed structural/compositional changes that simultaneously optimize these properties. Our analysis of such extensive QM property data provides compelling evidence for an intrinsic “freedom of design” in MPS, and indicates that rational design of molecules with a diverse array of targeted QM properties is quite feasible.
Band splitting and plurality of excitons in Ruddlesden-Popper metal halides
Authors: Folpini Giulia , Palummo Maurizia , Cortecchia Daniele , Moretti Luca , Cerullo Giulio , Petrozza Annamaria , Giorgi Giacomo , Srimath Kandada Ajay Ram
Published: February 2022

The organic-inorganic interactions within the hybrid lattice of two-dimensional Ruddlesden-Popper metal halides(RPMH) have consequences on the structural and electronic properties of the material. Such interactions have been primarily investigated through a library of organic cations, keeping the inorganic lead halide lattice component intact. Here, we demonstrate that the role of the organic-inorganic interactions in electronic processes can also be effectively manipulated by the metal cation, particularly moving from heavier lead to lighter tin. We perform in-depth spectroscopic and theoretical analysis of prototypical tin-based RPMH, in which we identify the presence multiple resonances in the optical spectra, which correspond to distinct exciton series. We show that the higher energy excitonic series are composed of electronic transitions from a lower lying valence band which originates from variations in the coordination geometries of the metal halide octahedra induced by subtle changes in the organic-inorganic interactions. Our studies indicate that the deformation induced splitting of the carrier bands is ubiquitous to the Ruddlesden-Popper architectures, although the splitting energies are substantially higher in the tin based systems.
Understanding and Overcoming Proximity Effects in Multi-Spot Two-Photon Direct Laser Writing
Authors: Arnoux Caroline , Perez-Covarrubias Luis-Adrian , Khaldi Alexandre , Carlier Quentin , Baldeck Patrice , Heggarty Kevin , Banyasz Akos , Monnereau Cyrille
Published: February 2022

Although additive manufacturing using multi-photon direct laser writing is nowadays considered as a major tool in the fabrication of future nano/micro-objects and optical components, it is currently limited by the low throughput of the writing process. To circumvent this issue, massive parallelization of the write process is a very promising avenue. However, simultaneous writing of structures in close spatial proximity generates fabrication artefacts, collectively referred to as “proximity effects”, which strongly limit the accessible structure resolution. In this work, we systematically investigate the experimental parameters that influence these effects using specifically designed N×N spot diffractive optical elements. Through computer simulations, we show that these effects can be modeled remarkably successfully simply by taking Point Spread Function overlap and diffusion processes into account. We illustrate the usefulness of the concept by designing a parallel write approach giving access to periodic structures with short inter-object distances while very largely overcoming proximity effects.
Development of Diazaborines as ROS Sensitive Linkers for the Construction of Stimuli-Responsive Antibody Drug Conjugates
Authors: Gois Pedro , António João , Carvalho Joana , André Ana , Dias Joana , Faustino Hélio , Lopes Ricardo , Veiros Luis , Bernardes Gonçalo , Silva Frederico
Published: February 2022

Antibody-drug conjugates (ADCs) are a new class of therapeutics that combine the lethality of potent cytotoxic drugs with the targeting ability of antibodies to selectively deliver drugs to cancer cells. The synthesis of ADCs is challenging, and studies in this area show that their therapeutic effect is highly dependent on the chemistries used to connect both functions. Therefore, the linker evolved in recent years from being a simple chemical spacer to a functional structure that controls the potency and selectivity of ADCs. The linker provides a platform to integrate mechanisms to access synthetic homogeneity, stability in circulation and more importantly the installation of chemical units that release the drug as a response to the disease chemical environment. In this study we show for the first time the synthesis of a reactive-oxygen-species (ROS) responsive ADC (VL-DAB31-SN-38) that is highly selective and cytotoxic to B-cell lymphoma (CLBL-1 cell line, IC50 value of 54.1 nM). The synthesis of this ADC was possible due to the discovery that diazaborines (DABs) are a very effective ROS responsive unit (0.422 and 0.103M-1S-1 with 100 and 10 equiv. of H2O2 respectively), that is also very stable in buffer (over 14 days at different pHs) and in plasma (over 5 days). DFT calculation performed on this system revealed a favourable energetic profile (ΔGR = –74.3 kcal/mol) similar to the oxidation mechanism of aromatic boronic acids. DABs very fast formation rate and modularity enabled the construction of different ROS responsive linkers featuring self-immolative modules, bioorthogonal functions and bioconjugation handles. These structures were used in the site-selective functionalization of a VL antibody and in the construction of the homogeneous ADC. The enclosed ROS-responsive linker technology based on DABs, is expected to become a valuable tool to prepare stimuli responsive therapeutic materials, as ROS is a very important hallmark in several important diseases
Catalytic Reduction of Dinitrogen to Ammonia and Hydrazine Using Iron–Dinitrogen Complexes Bearing Anionic Benzene-Based PCP-type Pincer Ligands
Authors: Kuriyama Shogo , Kato Takeru , Tanaka Hiromasa , Konomi Asuka , Yoshizawa Kazunari , Nishibayashi Yoshiaki
Published: February 2022

Among synthetic models of nitrogenases, iron–dinitrogen complexes with a Fe–C bond have attracted increasing attention in recent years. Here we report the synthesis of square-planar iron(I)–dinitrogen complexes supported by anionic benzene-based PCP- and POCOP-type pincer ligands as carbon donors. These complexes catalyze the formation of ammonia and hydrazine from the reaction of dinitrogen (1 atm) with a reductant and a proton source at -78 °C, producing up to 252 equiv of ammonia and 68 equiv of hydrazine (388 equiv of fixed N atom) based on the iron atom of the catalyst. Anionic iron(0)–dinitrogen complexes, considered an essential reactive species in the catalytic reaction, are newly isolated from the reduction of the corresponding iron(I)–dinitrogen complexes. This study examines their reactivity using experiments and DFT calculations.
Ultrafast and Selective Labeling of Endogenous Proteins Using Affinity-based Benzotriazole Chemistry
Authors: Xin Xiaoyi , Zhang Yu , Gaetani Massimiliano , Lundström Susanna , Zubarev Roman , Zhou Yuan , Corkery Dale , Wu Yaowen
Published: February 2022

Chemical modification of proteins is enormously useful for characterizing protein function in complex biological systems and for drug development. Selective labeling of native or endogenous proteins is challenging owing to the existence of distinct functional groups in proteins and in living systems. Chemistry for rapid and selective labeling of proteins remains in high demand. Here we have developed novel affinity labeling probes using benzotriazole (BTA) chemistry. We showed that affinity-based BTA probes selectively and covalently label a lysine residue in the vicinity of the ligand binding site of a target protein with a reaction half-time of 28-42 s. The reaction rate constant is comparable to the fastest biorthogonal chemistry. This approach was used to selectively label different cytosolic and membrane proteins in vitro and in live cells. BTA chemistry could be widely useful for labeling of native/endogenous proteins, target identification and development of covalent inhibitors.
The Ion Pair Thermal Model of MALDI MS
Authors: Fang Shiyue
Published: February 2022

The ion pair thermal model for MALDI MS is described. Key elements of the model include thermal desorption and ionization, strong tendency to neutralization via ion pair formation and proton transfer in the gas phase, thermal equilibrium, overall charge neutral plume, and thermal energy assisted free ion generation via ion pair separation by ion extraction potential. The quantities of ions in the solid sample and in the gaseous plume are estimated. Ion yields of different classes of molecules including peptides, nucleic acids, permanent salts and neutral molecules are estimated at the macroscale and single ion pair levels. The estimated ion yields are close to experimentally observed values under certain assumptions. Explanations of several observations in MALDI MS such as mostly single-charged peaks, improvement of spectra by ammonium cation, and ion suppression are provided. We expect that the model can give insights for the design of new conditions and systems for improving the sensitivity and resolution of MALDI MS and improving its capability and reliability to analyze large biomolecules.
Using Constrained Density Functional Theory to Track Proton Transfers and to Sample Their Associated Free Energy Surface
Authors: Voth Gregory , Li Chenghan
Published: February 2022

The ab initio molecular dynamics (AIMD) and quantum mechanics/molecular mechanics (QM/MM) methods are powerful tools for studying proton solvation, transfer, and transport processes in various environments. However, due to the high computational cost of such methods, achieving sufficient sampling of rare events involving excess proton motion – especially when Grotthuss proton shuttling is involved – usually requires enhanced free energy sampling methods to obtain informative results. Moreover, an appropriate collective variable (CV) that describes the effective position of the net positive charge defect associated with an excess proton is essential for both tracking the trajectory of the defect and for the free energy sampling of the processes associated with the resulting proton transfer and transport. In this work, such a CV is derived from first principles using constrained density functional theory (CDFT). This CV is applicable to a broad array of proton transport and transfer processes as studied via AIMD and QM/MM simulation.
Bridging the Gap between H- and J-Aggregates: Classification and Supramolecular Tunability for Excitonic Band Structures in 2-Dimensional Molecular Aggregates
Authors: Deshmukh Arundhati , Geue Niklas , Bardbury Nadine , Atallah Timothy , Chuang Chern , Pengshung Monica , Cao Jianshu , Sletten Ellen , Neuhauser Daniel , Caram Justin
Published: February 2022

Molecular aggregates with long-range excitonic couplings have drastically different photophysical properties compared to their monomer counterparts. From Kasha’s model for 1-dimensional systems, positive or negative excitonic couplings lead to blue or red shifted optical spectra with respect to the monomers, labelled H-and J-aggregates respectively. The overall excitonic couplings in higher dimensional systems are much more complicated and cannot be simply classified from their spectral shifts alone. Here, we provide a unified classification for extended 2D aggregates using temperature dependent peak shifts, thermal broadening and quantum yields. We discuss the examples of six 2D aggregates with J-like absorption spectra but quite drastic changes quantum yields and superradiance. We find the origin of the differences is, in fact, a different excitonic band structure where the bright state is lower energy than the monomer but still away from the band edge. We call this an ‘I-aggregate’. Our results provide a description of the complex excitonic behaviors that cannot be explained solely on Kasha’s model. Further, such properties can be tuned with the packing geometries within the aggregates providing supramolecular pathways for controlling them. This will allow for precise optimizations of aggregate properties in their applications across the areas of optoelectronics, photonics, excitonic energy transfer, and shortwave infrared technologies.
Bridging the Gap between H- and J-Aggregates: Classification and Supramolecular Tunability for Excitonic Band Structures in 2-Dimensional Molecular Aggregates
Authors: Deshmukh Arundhati , Geue Niklas , Bradbury Nadine , Atallah Timothy , Chuang Chern , Pengshung Monica , Cao Jianshu , Sletten Ellen , Neuhauser Daniel , Caram Justin
Published: February 2022

Molecular aggregates with long-range excitonic couplings have drastically different photophysical properties compared to their monomer counterparts. From Kasha’s model for 1-dimensional systems, positive or negative excitonic couplings lead to blue or red shifted optical spectra with respect to the monomers, labelled H-and J-aggregates respectively. The overall excitonic couplings in higher dimensional systems are much more complicated and cannot be simply classified from their spectral shifts alone. Here, we provide a unified classification for extended 2D aggregates using temperature dependent peak shifts, thermal broadening and quantum yields. We discuss the examples of six 2D aggregates with J-like absorption spectra but quite drastic changes quantum yields and superradiance. We find the origin of the differences is, in fact, a different excitonic band structure where the bright state is lower energy than the monomer but still away from the band edge. We call this an ‘I-aggregate’. Our results provide a description of the complex excitonic behaviors that cannot be explained solely on Kasha’s model. Further, such properties can be tuned with the packing geometries within the aggregates providing supramolecular pathways for controlling them. This will allow for precise optimizations of aggregate properties in their applications across the areas of optoelectronics, photonics, excitonic energy transfer, and shortwave infrared technologies.
Artemisinin and Quinoline Hybrid Compounds Inhibit Replication of SARS-CoV-2 In Vitro
Authors: Herrmann Lars , Yaremenko Ivan , Çapcı Aysun , Struwe Julia , Hodek Jan , Belyakova Yulia , Radulov Peter , Stepanov Grigoriy , Weber Jan , Terent'ev Alexander , Ackermann Lutz , Tsogoeva Svetlana
Published: February 2022

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause life-threatening diseases in millions of people worldwide and there is an urgent need for antiviral agents against this infection. While in vitro activities of artemisinins (containing endoperoxide moiety) and chloroquine (containing quinoline subunit) against SARS-CoV-2 have recently been demonstrated, no study of artemisinin- and quinoline-based hybrids has been reported yet. However, the hybrid drug’s properties can be improved compared to its parent compounds and effective new agents can be obtained by modification/hybridization of existing drugs. In this study, fifteen artemisinin- and quinoline-containing hybrid compounds were synthesized and analyzed in vitro for the first time for their inhibitory activity against SARS-CoV-2 in a cytopathic effect reduction assay. All artesunic acid-containing hybrids display superior potency against SARS-CoV-2 (EC50 values 7.8 – 46 μM) and show low or no cytotoxic effects on Vero E6 cells (CC50 up to 110 µM). The most active artesunic acid-derived hybrid is significantly more potent in vitro (EC50 = 7.8 µM) than its parent compound artesunic acid (EC50 >50 µM). Among quinoline-based new compounds, quinoline-adamantane (EC50 = 1.5 μM) is the most efficient in vitro outperforming the reference drugs chloroquine (EC50 = 3.8 µM) and remdesivir (EC50 = 4.0 µM).
Metal-Free Stereoselective Cationic Polymerization of Vinyl Ethers by Employing a Confined Brønsted Acid as the Catalyst
Authors: Yang Zan , Zhang Xun , Jiang Yu , Ma Qiang , Liao Saihu
Published: February 2022

The properties of poly(vinyl ether)s (PVEs) are highly dependent on their tacticity, and the appealing thermoplastics features of isotactic PVEs have drawn considerable efforts to develop stereoselective cationic polymerization methods to access this class of polymers. However, re-ported methods that could achieve a high degree of tacticity control are limited to process employing metal-based Lewis acids, and with various limitations on catalyst loading, monomer scope, etc. Here, we introduce a metal-free stereoselective cationic polymerization of vinyl ethers by employing a class of chiral confined Brønsted acids, imidodiphos-phorimidates (IDPis), as the catalyst. This organocatalytic approach features its metal free conditions, high efficiency, high stereoselectivity, single catalyst system, operation simplicity, etc.
Two Faces of the Two Phase Thermodynamic Model
Authors: Madarász Ádám , Hamza Andrea , Ferenc Dávid , Bakó Imre
Published: February 2022

The quantum harmonic model and the two-phase thermodynamics method (2PT) are widely used to obtain quantum corrected properties such as isobaric heat capacities or molar entropies. 2PT heat capacities were calculated inconsistently in the literature. For water the classical heat capacity was also considered, but for organic liquids it was omitted. We reanalyzed the performance of different quantum corrections on the heat capacities of common organic solvents against experimental data. We have pointed out serious flaws in previous 2PT studies. The vibrational density of states was calculated incorrectly causing 39 % relative error in diffusion coefficients and 45 % error in the 2PT heat capacities. The wrong conversion of isobaric isochoric heat capacity also caused about 40 % error but in the other direction. We have introduced the concept of anharmonic correction (AC) which is simply the deviation of the classical heat capacity from that of the harmonic oscillator model. This anharmonic contribution is around +30-40 J/mol/K for water depending on the water model and -8-10 J/mol/K for hydrocarbons and halocarbons. AC is unrealistically large, +40 J/K/mol for alcohols and amines indicating some deficiency of the OPLS force field. The accuracy of the computations was also assessed with the determination of the self-diffusion coefficients.
Conjugation of proapoptotic peptides with folate and cyanine dyes for enhanced potency and selectivity towards tumor cell lines
Authors: Cardella Davide , Luk Louis Yu Pan , Tsai Yu-Hsuan
Published: February 2022

Despite continuous advances, anticancer therapy still faces several technical hurdles such as selectivity on cellular and subcellular targets of therapeutics. Toward addressing these limitations, we have combined the use of proapoptotic peptides, cyanine dyes and folate to target the mitochondria of tumor cells. Hence, a series of proapoptotic peptides and their conjugates with a cyanine dye and/or a folate were prepared via solid-phase peptide synthesis (SPPS) and their activity tested in different mammalian cell lines. Compounds bearing either a cyanine dye or folate were found to be more cytotoxic than the parent peptides or more selective towards cells overexpressing the folate receptor α, which is commonly found on the surface of tumor cells. Nevertheless, constructs containing both components showed diminished potency and selectivity.
Dynamic Polymer Free Volume Monitored by Single-Molecule Spectroscopy of a Dual Fluorescent Flapping Dopant
Authors: Saito Shohei
Published: February 2022

Single-molecule spectroscopy (SMS) of a dual-fluorescent flapping molecular probe (N-FLAP) enabled real-time nanoscale monitoring of local free-volume dynamics in polystyrenes. The SMS study was realized by structural modification of a previously reported flapping molecule by nitrogen substitution, leading to 20 times increased brightness of the probe. In a polystyrene thin film at the temperature of 5 K above the glass transition, the spectra of a single N-FLAP molecule undergo frequent jumps between short- and long-wavelength forms, the latter one indicating planarization of the molecule in the excited state. The spectral jumps were statistically analyzed to reveal the dynamics of molecular environment. The analysis together with MD and QM/MM calculations demonstrate that the planarization of the flapping probe occurs only when sufficiently large polymer free volume of more than, at least, 200 Å^3 is available close to the molecule, and that such free volume lasts for an average of 1.17 seconds.
Property-Optimized Gaussian Basis Sets for Lanthanides
Authors: Rappoport Dmitrij
Published: February 2022

Property-optimized Gaussian basis sets of split-valence, triple-zeta and quadruple-zeta valence quality are developed for the lanthanides Ce–Lu for use with small-core relativistic effective core potentials. They are constructed in a systematic fashion by augmenting def2 orbital basis sets with diffuse basis functions and minimizing negative static isotropic polarizabilities of lanthanide atoms with respect to basis set exponents within the unrestricted Hartree–Fock method. The basis set quality is assessed using a test set of 70 molecules containing the lanthanides in their common oxidation states and f electron occupations. 5d orbital occupation turns out to be the determining factor for the basis set convergence of polarizabilities in lanthanide atoms and the molecular test set. Therefore, two series of property-optimized basis sets are defined. The augmented def2-SVPD, def2-TZVPPD, and def2-QZVPPD basis sets balance the accuracy of polarizabilities across lanthanide oxidation states. The relative errors in atomic and molecular polarizability calculations are ≤8% for augmented split-valence basis sets, ≤2.5% for augmented triple-zeta valence basis sets, and ≤1% for augmented quadruple-zeta valence basis sets. In addition, extended def2-TZVPPDD and def2-QZVPPDD are provided for accurate calculations of lanthanide atoms and neutral clusters. The property-optimized basis sets developed in this work are shown to accurately reproduce electronic absorption spectra of a series of LnCp'3- complexes (Cp' = C5H4SiMe3, Ln = Ce–Nd, Sm) with time-dependent density functional theory.
A Crystalline Tri-thorium Cluster: When Metal σ-Aromaticity Just Isn’t Enough
Authors: Szczepanik Dariusz
Published: February 2022

This study provides multiple incontrovertible evidences that the crystalline tri-thorium cluster recently synthesized by Liddle and co-workers is truly σ-aromatic, but the role of aromaticity is limited to shape molecular-response properties rather than stability. The latter is shown to be determined by the unprecedented multicenter charge-shift bonding pattern involving thorium and chlorine atoms. This study extends the range of the charge-shift bonding beyond transition metals, and may have potential implications for future attempts to design and synthesize new stable actinide complexes.
Evaluation of a Bruker timsTOF Pro for Native Mass Spectrometry
Authors: Panczyk Erin , Snyder Dalton , Liu Fanny , Lin Yu-Fu , Ridgeway Mark , Park Mel , Bleiholder Christian , Wysocki Vicki
Published: February 2022

Mass spectrometry-based assays in structural biology studies typically measure either intact or digested proteins. Traditionally, there are different mass spectrometers dedicated for such measurements: those focused on the rapid analysis of small molecules, such as digested peptides, and those designed for high mass intact analysis. The Bruker timsTOF Pro mass spectrometer (ion mobility-quadrupole-time of flight platform, IM-Q-TOF), has become widely utilized for the analysis of small molecules in the fields of proteomics and metabolomics, with ion mobility spectrometry offering an additional stage of ion separation coupled to liquid chromatography. While this instrument has proven capabilities for small molecule analysis, the ability to perform high-quality native mass spectrometry of intact protein complexes remains largely uninvestigated. Here, we evaluate this IM-Q-TOF platform for the analysis of intact proteins and non-covalently bound protein complexes as small as 12 kDa (cytochrome c) and as large as 801 kDa (GroEL), utilizing the full range of ion mobility, MS, and MS/MS (in-source cleanup and collision cell CID) experiments available on this platform. In-source activation and collision cell CID were found to be robust capabilities for both small and large complexes. Nonetheless, the TIMS analyzer was soft enough to preserve protein-ligand interactions between 1,3-benzenedisulfonamide and carbonic anhydrase. TIMS-CID was performed on the protein complexes streptavidin (53 kDa), avidin (68 kDa) and cholera toxin B (CTB, 58 kDa). Pyruvate kinase and GroEL were beyond the trapping capabilities of the commercial TIMS analyzer. Although quadrupole selection is limited to m/z 3000 by the manufacturer, ions of significantly higher m/z can be transmitted and studied. The present results show that the commercially available Bruker IM-Q-TOF platform can be used for both omics and native mass spectrometry applications; however, modifications to the commercial RF drivers for the TIMS analyzer and quadrupole will be required if protein complexes greater than a few tens of kDa are of interest.
Biodegradable Polyimidazole Particles as Contrast Agents produced by Direct Arylation Polymerization
Authors: Jansen Felicitas , Schuster Philipp , Lamla Markus , Trautwein Christian , Kühne Alexander
Published: February 2022

Conjugated polymer particles provide an important platform for the development of theranostic nanoagents. However, the number of biocompatible and foremost biodegradable π-conjugated polymers is limited. Imidazole is a π-conjugated motif that is abundant in biological systems. Oxidative degradation of imidazole is present in nature via enzymatic or free radical processes. In this work, we introduce polymer particles consisting purely of polyimidazole. We employ direct arylation polymerization and adapt it to a dispersion polymerization protocol to yield uniform and narrowly dispersed nanoparticles. We employ this mechanism to produce linear and crosslinked polymer particles to tune the optical properties from fluorescent to photoacoustically active. We show that the particles can be degraded by H2O2 as well as by reactive oxygen species produced by cells and we detect the degradation products. Altogether our results suggest that polyimidazole particles represent ideal candidates for theranostic applications.
Fast and Automated Identification of Reactions with Low Barriers: The Decomposition of 3-Hydroperoxypropanal
Authors: Rasmussen Maria Harris , Madsen Mads , Jensen Jan H.
Published: February 2022

We show how fast semiempirical QM methods can be used to significantly decrease the CPU requirements for automated reaction mechanism discovery, using two different method for generating reaction products: graph-based systematic enumeration of all possible products and the meta-dynamics approach by Grimme (J. Chem. Theory. Comput. 2019, 15, 2847). We test the two approaches on the low-barrier reactions of 3-hydroperoxypropanal, which have been studied by a large variety of reaction discovery approaches and therefore provides a good benchmark. By using PM3 and GFN2-xTB for reaction energy and barrier screening the systematic approach identifies 64 reactions (out of 27,577 possible reactions) for DFT refinement, which in turn identifies the three reactions with lowest barriers plus a previously undiscovered reaction. With optimised hyperparameters meta-dynamics followed by PM3/GFN2-xTB-based screening identifies 15 reactions for DFT refinement, which in turn identifies the three reactions with lowest barrier. The number of DFT refinements can be further reduced to as little as six for both approaches by first verifying the transition states with GFN1-xTB. The main conclusion is that the semiempirical methods are accurate and fast enough to automatically identify promising candidates for DFT refinement for the low barrier reactions of 3-hydroperoxypropanal in about 15-30 minutes using relatively modest computational resources.
Donor-Acceptor Pyridinium Salts for Photo-Induced Electron Transfer Driven Modification of Tryptophan in Peptides, Proteins, and Proteomes using Visible Light
Authors: Hoopes Caleb , Garcia Francisco , Sarkar Akash , Kuehl Nicholas , Barkan David , Collins Nicole , Hsu Chien-Hsang , Jones Michael , Schirle Markus , Taylor Michael
Published: February 2022

Tryptophan (Trp) plays a variety of critical functional roles in protein biochemistry however, owing to its low natural frequency and poor nucleophilicity, the design of effective methods for both single protein bioconjugation at Trp as well as for in situ chemoproteomic profiling re-mains a challenge. Here, we report a method for covalent Trp modification that is suitable for both scenarios by invoking photo-induced electron transfer (PET) as a means of driving efficient reactivity. We have engineered biaryl N-carbamoyl pyridinium salts that possess a donor-acceptor relationship enabling optical triggering with visible light whilst simultaneously attenuating the probe’s photo-oxidation potential in order to prevent photodegradation. This probe was assayed against a small bank of eight peptides and proteins, where it was found that micromolar concentrations of probe and short irradiation times (10-60 min) with violet light enabled efficient reactivity towards surface exposed Trp residues. The carbamate transferring group can be used to transfer useful functional groups to proteins including affinity tags and click handles. DFT calculations and other mechanistic analyses reveal correlations between excited state lifetimes, relative fluorescent quantum yields, and chemical reactivity. Biotinylated and azide-functionalized pyridinium salts were used for Trp profiling in HEK293T lysates and in situ in HEK293T cells using 450 nm LED irradiation. Peptide level enrichment from live cell labelling experiments identified 290 Trp modifications, with an 82% selectivity for Trp modification over other π-amino acids; demonstrating the ability of this method to identify and quantify reactive Trp residues from live cells.
Guest-induced misfolding of a crown-ether-functionalized ortho-phenylene
Authors: Peddi Sumalatha , Bookout Molly C. , Vemuri Gopi Nath , Hartley C. Scott
Published: February 2022

A crown-ether-functionalized o-phenylene tetramer has been synthesized and co-assembled with monotopic and ditopic, achiral and chiral secondary ammonium ion guests. NMR spectroscopy shows that the o-phenylene forms both 1:1 and 1:2 complexes with monotopic guests while remaining well-folded. Binding of an elongated ditopic guest, however, forces the o-phenylene to misfold by pulling the terminal rings apart. A chiral ditopic guest biases the o-phenylene twist sense.
Graph Neural Networks Bootstrapped for Synthetic Selection and Validation of Small Molecule Immunomodulators
Authors: Wijewardhane Prageeth R. , Jethava Krupal P. , Fine Jonathan A , Chopra Gaurav
Published: February 2022

The Programmed Cell Death Protein 1/Programmed Death-Ligand 1 (PD-1/PD-L1) interaction is an immune checkpoint utilized by cancer cells to enhance immune suppression. There is a huge need to develop small molecule drugs that are fast acting, cost effective, and readily bioavailable compared to antibodies. Unfortunately, synthesizing and validating large libraries of small- molecules to inhibit PD-1/PD-L1 interaction in a blind manner is both time-consuming and expensive. To improve this drug discovery pipeline, we have developed a machine learning methodology trained on patent data to identify, synthesize, and validate PD-1/PD-L1 small molecule inhibitors. Our model incorporates two features: docking scores to represent the energy of binding (E) as a global feature and sub-graph features through a graph neural network (GNN) of molecular topology to represent local features. This interaction energy-based Graph Neural Network (EGNN) model outperforms traditional machine learning methods and a simple GNN with a F1 score of 0.9524 and Cohen’s kappa score of 0.8861 for the hold out test set, suggesting that the topology of the small molecule, the structural interaction in the binding pocket, and chemical diversity of the training data are all important considerations for enhancing model performance. A Bootstrapped EGNN model was used to select compounds for synthesis and experimental validation with predicted high and low potency to inhibit PD-1/PD-L1 interaction. The potent inhibitor, (4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2- methylbenzyl)oxy)-2,6-dimethoxybenzyl)-D-serine, is a hybrid of two known bioactive scaffolds, with an IC50 of 339.9 nM that is comparatively better than the known bioactive compound. We conclude that our bootstrapped EGNN model will be useful to identify target-specific high potency molecules designed by scaffold hopping, a well-known medicinal chemistry technique.
Profiling of D-alanine production by the microbial isolates of rat gut microbiota
Authors: Lee Cindy J. , Qiu Tian A. , Hong Zhilai , Zhang Zhenkun , Min Yuhao , Zhang Linzixuan , Dai Lei , Zhao Huimin , Si Tong , Sweedler Jonathan V.
Published: February 2022

D-alanine (D-Ala) and several other D-amino acids (D-AAs), unusual amino acids present in mammals, act as hormones and neuromodulators in nervous and endocrine systems. Unlike the endogenously synthesized D-serine in animals, D-Ala may be from exogenous sources, e.g., diet and intestinal microorganisms. However, it is unclear if the capability to produce D-Ala and other D-AAs varies among different microbial strains in the gut. We isolated individual microorganisms of rat gut microbiota and profiled their D-AA secretion in vitro, focusing on D-Ala. Serial dilutions of intestinal content from adult male rats were plated on agar to obtain clonal cultures. Using MALDI-TOF MS for rapid strain typing, we identified 38 unique isolates, grouped into 11 species based on 16S rRNA gene sequences. We then used two-tier screening to profile bacterial D-AA secretion, combining a D-amino acid oxidase-based enzymatic assay for rapid assessment of overall D-AA amount, followed by chiral LC-MS/MS to quantify individual D-AAs, revealing 19 out of the 38 isolated strains as D-AA producers. LC-MS/MS analysis of the eight top D-AA producers showed high levels of D-Ala in all strains tested, with substantial inter- and intra-species variations. Though results from enzymatic assay and LC-MS/MS analysis aligned well, LC-MS/MS further revealed the existence of D-glutamate and D-aspartate, which are poor substrates for enzymatic assay. We observed large inter- and intra-species variation of D-AA secretion profiles from rat gut microbiome species, demonstrating the importance of chemical profiling of gut microbiota in addition to sequencing, furthering the idea that microbial metabolites modulate host physiology.
A General Strategy to the Intracellular Sensing of Glycosidases using AIE-Based Glycoclusters
Authors: Dong Lei , Zhang Min-Yu , Han Hai-Hao , Zang Yi , Chen Guo-Rong , Li Jia , He Xiao-Peng , Vidal Sebastien
Published: February 2022

Glycosidases, which are the enzymes responsible for removal of residual monosaccharides from glycoconjugates, are implicated in a myriad of biological and pathological events. The ability to detect sensitively the activity and spatiotemporal distribution of glycosidases in cells may facilitate the study of glycobiology, and add useful diagnostic tools. However, the currently developed fluorogenic probes for glycosidases are generally based on glycosylation of a phenol group of a donor-acceptor type fluorogen. This general molecular scaffold has potential drawbacks in terms of substrate scope, sensitivity because of aggregation-caused quenching (ACQ), and the inability for long-term cell tracking. Here, we developed glycoclusters characterized by aggregation-induced emission (AIE) properties as a general platform for the sensing of a variety of glycosidases. To overcome the low chemical reactivity during phenol glycosylation, we synthesized an AIE-based dye composed of tetraphenylethylene conjugated with dicyanomethylene-4H-pyran (TPE-DCM) with a red fluorescence emission. Subsequently, a pair of dendritic linkages was introduced to both sides of the fluorophore, to which six copies of different monosaccharides (D-glucose, D-galactose and L-fucose) were conjugated through azide-alkyne click chemistry. The resulting AIE-active glycoclusters were shown to be capable of (1) fluorogenic sensing of a diverse range of glycosidases including β-D-galactosidase, β-D-glucosidase and α-L-fucosidase through the AIE mechanism, (2) fluorescence imaging of the endogenous glycosidase activities in healthy and cancer cells, and during cell senescence, and (3) glycosidase-activated, long-term imaging of cells. The present study provides a general strategy to the functional imaging of glycosidase activities through the multivalent display of sugar epitopes of interest onto AIE-active dyes.
Membrane mixing and dynamics in hybrid POPC/PBd-PEO lipid/block co-polymer giant vesicles
Authors: Seneviratne Rashmi , Rappolt Michael , Jeuken Lars , Beales Paul
Published: February 2022

Lipids and block copolymers can individually self-assemble into vesicles, each with their own particular benefits and limitations. Combining polymers with lipids allows for further optimisation of the vesicle membranes for bionanotechnology applications. Here, POPC lipid is mixed with poly(1,2-butadiene-block-ethylene oxide) of two different molecular weights (PBd22-PEO14, Mr = 1800 g.mol-1 and PBd12-PEO11, Mr = 1150 g.mol-1) in order to investigate, how increasing the polymer fraction affects membrane mixing, hydration and fluidity. Intensity contributions of fluorescently labelled lipid and polymer within mixed GUV membranes confirm membrane homogeneity within the hybrids. General polarisation measurements of Laurdan in GUVs showed little change in membrane hydration as polymer fraction is increased, which suggests good structurally compatibility between lipids and polymers that gives rise to well-mixed vesicles. Membrane fluidity in hybrid GUVs was found to decrease non-linearly with increasing polymer fraction. However, the diffusion coefficients for the fluorescent polymer in hybrid membranes did not change significantly with increasing polymer content. While increasing the polymer fraction does reduce the movement of lipids through a polymer-rich matrix, insignificant difference in diffusion coefficients of the polymer suggests that its diffusion is minimally affected by increasing lipid composition in the range studied. These results lay further foundations for the wider development of hybrid vesicles with controlled properties for advanced biotechnologies.