Maximizing Aqueous Drug Encapsulation: Small Nanoparticles Formation Enabled by Glycopolymers Combining Glucose and Tyrosine.

Highly potent heterocyclic drugs are frequently poorly water soluble, leading to limited or abandoned further drug development. Nanoparticle technology offers a powerful delivery approach by enhancing the solubility and bioavailability of hydrophobic therapeutics. However, the common usage of organic solvents causes unwanted toxicity and process complexity, therefore limiting the scale-up of nanomedicine technology for clinical translation. Here, we show that an organic-solvent-free methodology for hydrophobic drug encapsulation can be obtained using polymers based on glucose and tyrosine. An aqueous solution based on a tyrosine-containing glycopolymer is able to dissolve solid dasatinib directly without adding an organic solvent, resulting in the formation of very small nanoparticles of around 10 nm loaded with up to 16 wt % of drug. This polymer is observed to function as both a drug solubilizer and a nanocarrier at the same time, offering a simple route for the delivery of insoluble drugs.

Binding of Per- and Polyfluoroalkyl Substances to ß-Lactoglobulin from Bovine Milk.

Per- and polyfluoroalkyl substances (PFAS) are known for their high environmental persistence and potential toxicity. The presence of PFAS has been reported in many dairy products. However, the mechanisms underlying the accumulation of PFAS in these products remain unclear. Here, we used native mass spectrometry and molecular dynamics simulations to probe the interactions between 19 PFAS of environmental concern and two isoforms of the major bovine whey protein ß-lactoglobulin (ß-LG). We observed that six of these PFAS bound to both protein isoforms with low- to mid-micromolar dissociation constants. Based on quantitative, competitive binding experiments with endogenous ligands, PFAS can bind orthosterically and preferentially to ß-LG's hydrophobic ligand-binding calyx. ß-Cyclodextrin can also suppress binding of PFAS to ß-LG owing to the ability of ß-cyclodextrin to directly sequester PFAS from solution. This research sheds light on PFAS-ß-LG binding, suggesting that such interactions could impact lipid-fatty acid transport in bovine mammary glands at high PFAS concentrations. Furthermore, our results highlight the potential use of ß-cyclodextrin in mitigating PFAS binding, providing insights toward the development of strategies to reduce PFAS accumulation in dairy products and other biological systems.

The Quality of Embedding Charges Is Critical for Convergence of Many-Body Expansions When BSSE Is Absent.

There is conflicting evidence in the literature concerning the benefits of charge embedding on the convergence of many-body expansions (MBEs). Using a systematic series of water and ion-water clusters of varying size, this study indicates that the effects of charge embedding can be masked by basis set superposition error (BSSE). When BSSE is removed, this study demonstrates that charge embedding can significantly accelerate MBE convergence, where the electrostatically embedded two-body method, EE-MBE(2), can often yield accuracy close to the four-body method, MBE(4). Contrary to previous studies on smaller systems, this work shows that the performance of EE-MBE is highly sensitive to the charge model, with the best performance obtained when the natural population analysis (NPA) charge model is used and generated at the same level of theory used in the subsystem and supersystem calculations. It was demonstrated that the "3c" composite method, PBEh-3c, yields NPA atomic charges that are in excellent agreement with those obtained from supersystem density functional theory calculations. The linear-scaling X-Polarization method provides a more general approach to estimating these supersystem QM atomic charges, but its performance depends on how the fragments are defined.

In Search of the Best Low-Cost Methods for Efficient Screening of Conformers.

Locating the lowest energy conformer is crucial for the accurate computation of equilibrium properties of molecular systems. This paper examines the performance of efficient low-cost methods in terms of the alignment and relative energies of their energy minima against the benchmark revDSD-PBEP86-D4/def2-TZVPP//MP2/cc-pVTZ potential energy surface. The low-cost methods considered include GFN-FF, GFN2-xTB, DFTB3, HF-3c, B97-3c, PBEh-3c, and r2SCAN-3c composite methods against a diverse test set of 20 compounds including alkanes, perfluoroalkyl molecules, peptides, open-shell radicals, and Zn(II) complexes of varying sizes. The "3c" composite methods are generally more accurate, but are at least 2-3 orders of magnitude more expensive than tight-binding methods which have energy minima that align well with the benchmark potential energy surface. The findings of this paper were further exploited to introduce a simple strategy involving Grimme's CENSO energy-sorting algorithm that resulted in up to an order of magnitude reduction in computational time for locating the lowest energy conformer on the revDSD-PBEP86-D4/def2-TZVPP//MP2/cc-pVTZ surface.

A High-capacity Benzoquinone Derivative Anode for All-organic Long-cycle Aqueous Proton Batteries.

Quinone compounds, with the ability to uptake protons, are promising electrodes for aqueous batteries. However, their application is limited by the mediocre working potential range and inferior rate performance. Herein, we examined quinones bearing different substituents, and for the first time introduce tetraamino-1,4-benzoquinone (TABQ) as anode material for proton batteries. The strong electron-donating amino groups can effectively narrow the band gap and negatively shift the redox potentials of quinone material. The protonation of amino groups and the amorphization of structure result in the formation of an intermolecular hydrogen-bond network, supporting Grotthuss-type proton conduction in the electrode with a low activation energy of 192.7 meV. The energy storage mechanism revealed by operando FT-IR and ex-situ XPS features a reversible quinone-hydroquinone conversion during cycling. TABQ demonstrates a remarkable specific capacity of 307 mAh g-1 at 1 A g-1, which is the highest among organic proton electrodes. An all-organic proton battery of TABQ//TCBQ has also been developed, achieving exceptional stability of 3500 cycles at room temperature and excellent performance at sub-zero temperatures.

MM/GBSA prediction of relative binding affinities of carbonic anhydrase inhibitors: effect of atomic charges and comparison with Autodock4Zn.

Carbonic anhydrase is an attractive drug target for the treatment of many diseases. This paper examines the ability of end-state MM/GBSA methods to rank inhibitors of carbonic anhydrase in terms of their binding affinities. The MM/GBSA binding energies were evaluated using different atomic charge schemes (Mulliken, ESP and NPA) at different levels of theories, including Hartree-Fock, B3LYP-D3(BJ), and M06-2X with the 6-31G(d,p) basis set. For a large test set of 32 diverse inhibitors, the use of B3LYP-D3(BJ) ESP atomic charges yielded the strongest correlation with experiment (R2 = 0.77). The use of the recently enhanced Autodock Vina and zinc optimised AD4Zn force field also predicted ligand binding affinities with moderately strong correlation (R2 = 0.64) at significantly lower computational cost. However, the docked poses deviate significantly from crystal structures. Overall, this study demonstrates the applicability of docking to estimate ligand binding affinities for a diverse range of CA inhibitors, and indicates that more theoretically robust MM/GBSA simulations show promise for improving the accuracy of predicted binding affinities, as long as a validated set of parameters is used.

High-Level Quantum Chemical Prediction of C-F Bond Dissociation Energies of Perfluoroalkyl Substances.

In this study, 550 C-F bond dissociation energies (BDEs) of a variety of per- and polyfluoroalkyl substances (PFASs) obtained from high-level DLPNO-CCSD(T)/CBS calculations were used to assess the accuracy of contemporary density functional theory (DFT) and semiempirical methods. DLPNO-CCSD(T)/CBS gas phase C-F BDEs fall between 404.9-550.7 kJ mol-1 and M06-2X and ωB97M-V in conjunction with the aug-cc-pVTZ basis set predicted BDEs closest to the benchmark level with a mean absolute deviation (MAD) of 7.3 and 8.3 kJ mol-1, respectively. It was observed that DFT prediction errors increase with the degree of fluorination and system size. As such, previous model chemistry recommendations based on smaller nonfluorinated systems may not be carried over to modeling the energetics of PFASs and related systems.

Simple Composite Approach to Efficiently Estimate Basis Set Limit CCSD(T) Harmonic Frequencies and Reaction Thermochemistry.

We introduce a simple strategy that combines the G3(MP2) composite method and explicitly correlated coupled cluster CCSD(T)-F12 method to efficiently estimate complete basis set CCSD(T) molecular geometries and harmonic vibrational frequencies at the cost of a double-ζ basis set calculation. Based on a large test set of 61 neutral, ionic, and open-shell molecules, and additionally 31 molecules in the HFREQ2014 data set, we demonstrate that this composite strategy has an average accuracy of 2 cm-1 or better relative to complete basis set CCSD(T) values. Using this approach, we estimated 696 CCSD(T)/CBS reaction energies of small to medium-sized systems containing up to 6 heavy atoms and confirmed existing approximations that use small basis set density functional theory methods [e.g., M06-2X/6-31+G(d)] to calculate thermal contributions to reaction enthalpies and Gibbs free energies that are accurate to within 0.2 kcal mol-1 on average.

Hydrogen-Bond Disrupting Electrolytes for Fast and Stable Proton Batteries.

Rechargeable aqueous proton batteries are promising competitors for the next generation of energy storage systems with the fast diffusion kinetics and wide availability of protons. However, poor cycling stability is a big challenge for proton batteries due to the attachment of water molecules to the electrode surface in acid electrolytes. Here, a hydrogen-bond disrupting electrolyte strategy to boost proton battery stability via simultaneously tuning the hydronium ion solvation sheath in the electrolyte and the electrode interface is reported. By mixing cryoprotectants such as glycerol with acids, hydrogen bonds involving water molecules are disrupted leading to a modified hydronium ion solvation sheaths and minimized water activity. Concomitantly, glycerol absorbs on the electrode surface and acts to protect the electrode surface from water. Fast and stable proton storage with high rate capability and long cycle life is thus achieved, even at temperatures as low as -50 °C. This electrolyte strategy may be universal and is likely to pave the way toward highly stable aqueous energy storage systems.

Molecular Crowding Electrolytes for Stable Proton Batteries.

Proton electrochemistry is promising for developing post-lithium energy storage devices with high capacity and rate capability. However, some electrode materials are vulnerable because of the co-intercalation of free water molecules in traditional acid electrolytes, resulting in rapid capacity fading. Here, the authors report a molecular crowding electrolyte with the usage of poly(ethylene glycol) (PEG) as a crowding agent, achieving fast and stable electrochemical proton storage and expanded working potential window (3.2 V). Spectroscopic characterisations reveal the formation of hydrogen bonds between water and PEG molecules, which is beneficial for confining the activity of water molecules. Molecular dynamics simulations confirm a significant decrease of free water fraction in the molecular crowding electrolyte. Dynamic structural evolution of the MoO3 anode is studied by in-situ synchrotron X-ray diffraction (XRD), revealing a reversible multi-step naked proton (de)intercalation mechanism. Surficial adsorption of PEG molecules on MoO3 anode works in synergy to alleviate the destructive effect of concurrent water desolvation, thereby achieving enhanced cycling stability. This strategy offers possibilities of practical applications of proton electrochemistry thanks to the low-cost and eco-friendly nature of PEG additives.

Development of an Albumin-Polymer Bioconjugate via Covalent Conjugation and Supramolecular Interactions.

Preexisting serum albumin-polymer bioconjugates have been formed either through covalent conjugation or supramolecular interactions. However, the viability of producing a bioconjugate where both covalent conjugation and supramolecular interactions have been adopted is yet to be explored. In this work, the noncovalent interaction of two polymers bearing fatty acid-based end-functionalities were compared and the superior binder was carried forward for testing with serum albumin that possessed a polymer conjugated to its Cys34 residue. The studies demonstrated that an albumin-polymer bioconjugate equipped with polymers via both covalent and supramolecular interactions can be successfully achieved.

Quantum Chemical Prediction of the Acidities of Sulfonamide Inhibitors of Carbonic Anhydrase.

This study examined two pKa calculation approaches (direct and proton exchange schemes) that employ high-level quantum chemical methods and implicit solvent models to predict aqueous Brønsted acidities of a large set of sulfonamides. For gas-phase deprotonation energies, the DSD-PBEP86-D3(BJ) double-hybrid functional provided the best agreement with the LNO-CCSD(T)/CBS benchmark with a mean absolute deviation less than 2 kJ mol-1 when the aug-cc-pVTZ or larger basis sets are used. For a large test set of 54 primary and secondary sulfonamides, the use of the DSD-PBEP86-D3(BJ)/aug-cc-pVTZ level of theory in conjunction with SM12 solvation free energies predict their pKa values with a mean accuracy of 0.9 units. In comparison, the SMD and ADF-COSMO-RS models have slightly higher mean errors of 1.4 and 1.1 pKa units provided that the proton exchange scheme was employed to cancel the systematic errors in these models. The performance of these protocols was less ideal when applied to sulfonic acids, sulfamates, and N-substituted sulfonamides, indicating that the degree of error cancellation is sensitive to the chemical environment around the -NH2 head group. The validated protocols were then used to estimate the pKa values of arylsulfonamide carbonic anhydrase inhibitors, which are used to correct their experimentally measured binding free energies to account for deprotonation of the sulfonamide group upon binding to the enzyme. These corrected values did not have a significant impact on the correlation with MMGBSA binding free energies obtained from classical MD simulations where the ligand is usually considered in the deprotonated form.

"Water-in-Sugar" Electrolytes Enable Ultrafast and Stable Electrochemical Naked Proton Storage.

Proton is an ideal charge carrier for rechargeable batteries due to its small ionic radius, ultrafast diffusion kinetics and wide availability. However, in commonly used acid electrolytes, the co-interaction of polarized water and proton (namely hydronium) with electrode materials often causes electrode structural distortions. The hydronium adsorption on electrode surfaces also facilitates hydrogen evolution as an unwanted side reaction. Here, a "water-in-sugar" electrolyte with high concentration of glucose dissolved in acid to enable the naked proton intercalation, as well as an extended 3.9 V working potential window, is shown. A glucose-derived organic thin film is formed on electrode surface upon cycling. Molecular dynamics simulations reveal the significant decrease of free water in bulk electrolytes, while density functional theory calculations indicate that glucose preferentially binds to the electrode surface which can inhibit water adsorption. The scarcity of free water and the protective organic film work in synergy to suppress water interactions with the electrode surface, which enables the naked proton (de)intercalation. The "water-in-sugar" electrolyte significantly enhances a MoO3 electrode for stable cycling over 100 000 times. This facile electrolyte approach opens new avenues to aqueous electrochemistry and energy storage devices.

Diaminomethylenemalononitriles and Diaminomethyleneindanediones as Dual Hydrogen Bond Donors for Anion Recognition.

Diaminomethylenemalononitriles (DMMs) and diaminomethyleneindanediones (DMIs) are dual H-bond donors that have previously been used as organocatalysts, but their anion binding ability has not been investigated. We report the synthesis of both alkyl- and aryl-substituted DMMs and DMIs, together with a comparison of their anion binding ability with that of the analogous thioureas. The DMMs display affinity for monovalent anions, with similar anion binding affinities observed to that of the thioureas in acetonitrile, albeit with differing trends for the N,N'-dialkyl versus N,N'-diaryl compounds. In contrast, the DMIs do not bind to monovalent anions under similar conditions as a result of conformational locking through the formation of intramolecular H-bonds. This can be overcome upon addition of sulfate ions, and binding of sulfate is enhanced in a more competitive solvent (DMSO).

Accurate Quantum Chemical Prediction of Gas-Phase Anion Binding Affinities and Their Structure-Binding Relationships.

This paper systematically examines the performance of contemporary wavefunction and density functional theory methods to identify robust and cost-efficient methods for predicting gas-phase anion binding energies. This includes the local coupled cluster LNO-CCSD(T) and DLPNO-CCSD(T), as well as double-hybrid DSD-PBEP86-D3(BJ) and various hybrid functionals M06-2X, B3LYP-D3(BJ), ωB97M-V, and ωB97X-V. The focus is on dual-hydrogen-bonding anion receptors that are commonly found in supramolecular chemistry and organocatalysis, namely, (thio)ureas, deltamides, (thio)squaramides, and croconamides as well as the yet-to-be-explored rhodizonamides. Of the methods examined, M06-2X emerged as the overall best performing method as the other functionals including DSD-PBEP86-D3(BJ) and the local coupled cluster DLPNO-CCSD(T) method displayed systematic errors that increase with the degree of carbonylation of the receptors. Hybrid ONIOM models that employed semiempirical methods (PM7, GFN1-xTB, and GFN2-xTB) and "threefold"-corrected small-basis set potentials (HF-3c, B97-3c, and PBEh-3c) were explored, and the best models resulted in 50- to 500-fold reduction in CPU time compared to W1-local. These calculations provide important insight into the structure-binding relationships where there is a direct correlation between Brønsted acidity and anion binding affinity, though the strength of the correlation also depends on other factors such as hydrogen-bonding geometry and the geometrical distortion that the receptor needs to undergo to bind the anion.

Accuracy of DLPNO-CCSD(T): Effect of Basis Set and System Size.

The DLPNO-CCSD(T) method is designed to study large molecular systems at significantly reduced cost relative to its canonical counterpart. However, the error in this approach is also size-extensive and relies on cancellation of errors for the calculation of relative energies. This work provides a direct comparison of canonical CCSD(T) and TightPNO DLPNO-CCSD(T) calculations of reaction energies and barriers of a broad range of chemical reactions. The dataset includes acidities, anion binding affinities, enolization, Diels-Alder, nucleophilic substitution, and atom transfer reactions and complements existing theoretical datasets in terms of system size as well as new reaction types (e.g., anion binding affinities and chlorine atom transfer reactions). The performance of DLPNO-CCSD(T) was further examined with respect to systematic variation of basis set and system size and amounts of nonbonded interaction present in the system. The errors in the DLPNO-CCSD(T) were found to be relatively insensitive to the choice of basis set for small systems but increase monotonically with system size. Additionally, calculations of barriers appear to be more challenging than reaction energies with errors exceeding 5 kJ mol-1 for many Diels-Alder reactions. Further tests on three realistic organic reactions reveal the impact of the DLPNO approximation in calculating absolute and relative barriers that are important for predictions such as stereoselectivity.

Eigenvector centrality for characterization of protein allosteric pathways.

Determining the principal energy-transfer pathways responsible for allosteric communication in biomolecules remains challenging, partially due to the intrinsic complexity of the systems and the lack of effective characterization methods. In this work, we introduce the eigenvector centrality metric based on mutual information to elucidate allosteric mechanisms that regulate enzymatic activity. Moreover, we propose a strategy to characterize the range of correlations that underlie the allosteric processes. We use the V-type allosteric enzyme imidazole glycerol phosphate synthase (IGPS) to test the proposed methodology. The eigenvector centrality method identifies key amino acid residues of IGPS with high susceptibility to effector binding. The findings are validated by solution NMR measurements yielding important biological insights, including direct experimental evidence for interdomain motion, the central role played by helix h[Formula: see text], and the short-range nature of correlations responsible for the allosteric mechanism. Beyond insights on IGPS allosteric pathways and the nature of residues that could be targeted by therapeutic drugs or site-directed mutagenesis, the reported findings demonstrate the eigenvector centrality analysis as a general cost-effective methodology to gain fundamental understanding of allosteric mechanisms at the molecular level.

Polyphenylglyoxamide-Based Amphiphilic Small Molecular Peptidomimetics as Antibacterial Agents with Anti-Biofilm Activity.

The rapid emergence of drug-resistant bacteria is a major global health concern. Antimicrobial peptides (AMPs) and peptidomimetics have arisen as a new class of antibacterial agents in recent years in an attempt to overcome antibiotic resistance. A library of phenylglyoxamide-based small molecular peptidomimetics was synthesised by incorporating an N-alkylsulfonyl hydrophobic group with varying alkyl chain lengths and a hydrophilic cationic group into a glyoxamide core appended to phenyl ring systems. The quaternary ammonium iodide salts 16d and 17c showed excellent minimum inhibitory concentration (MIC) of 4 and 8 µM (2.9 and 5.6 µg/mL) against Staphylococcus aureus, respectively, while the guanidinium hydrochloride salt 34a showed an MIC of 16 µM (8.5 µg/mL) against Escherichia coli. Additionally, the quaternary ammonium iodide salt 17c inhibited 70% S. aureus biofilm formation at 16 µM. It also disrupted 44% of pre-established S. aureus biofilms at 32 µM and 28% of pre-established E. coli biofilms 64 µM, respectively. A cytoplasmic membrane permeability study indicated that the synthesised peptidomimetics acted via disruption and depolarisation of membranes. Moreover, the quaternary ammonium iodide salts 16d and 17c were non-toxic against human cells at their therapeutic dosages against S. aureus.

The Effect of Vicinal Difluorination on the Conformation and Potency of Histone Deacetylase Inhibitors.

Histone deacetylase enzymes (HDACs) are potential targets for the treatment of cancer and other diseases, but it is challenging to design isoform-selective agents. In this work, we created new analogs of two established but non-selective HDAC inhibitors. We decorated the central linker chains of the molecules with specifically positioned fluorine atoms in order to control the molecular conformations. The fluorinated analogs were screened against a panel of 11 HDAC isoforms, and minor differences in isoform selectivity patterns were observed.

Nontargeted Identification of Plasma Proteins O-, N-, and S-Transmethylated by O-Methyl Organophosphates.

Organophosphates (OPs) are used worldwide as pesticides. However, acute and chronic exposure to OPs can cause serious adverse health effects. The mechanism of delayed OP toxicity is thought to involve off-target inhibition of serine proteases, although the precise molecular details remain unclear owing to the lack of an analytical method for global detection of protein targets of OPs. Here, we report the development of a mass spectrometry method to identify OP-adducted proteins from complex mixtures in a nontargeted manner. Human plasma was incubated with the OP dichlorvos that was 50% isotopically labeled and 50% unlabeled. Proteins and protein adducts were extracted, digested, and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect "twin ions" of peptides that were covalently modified by a chemical reaction with dichlorvos. The LC-MS/MS data were processed by a blended data analytics software (Xenophile) to detect the amino acid residue sites of proteins that were covalently modified by exposure to OPs. We discovered that OPs can transmethylate the N, S, and O side chains of His, Cys, Glu, Asp, and Lys residues. For model systems, such transmethylation reactions were confirmed by LC-MS, nuclear magnetic resonance (NMR), and rationalized using electronic structure calculations. Methylation of the ubiquitous antioxidant glutathione by dichlorvos can decrease the reducing/oxidizing equilibrium of glutathione in liver extracts, which has been implicated in diseases and pathological conditions associated with delayed OP toxicity.