It has long been suggested that organic solvents disrupt the solvation shell around phosphate ions, which might facilitate calcium phosphate (CaP) nucleation. This would explain recent experimental findings where organic solvents─ethanol, isopropanol, and acetone─produce a denser CaP coating when synthesized on marble for conservation applications. In this work, computational methods are used to investigate the solvation shell of phosphate ions in mixed organic-aqueous solutions. Relative one-to-one interaction energies between the phosphates and solvents were calculated with density functional theory (DFT) and suggest that ethanol and isopropanol could displace water in the hydration sphere of PO43-, HPO42-, and H2PO4-. Classical molecular dynamics simulations with models benchmarked to these DFT interaction energies were then used to investigate solvation under bulk solvent conditions. In mixed organic-aqueous conditions, we find that the behavior in the phosphate solvation shell is dependent on the solvent and protonation state. More specifically, none of the three organic solvents consistently disrupts the hydration shell of the phosphates, which would correlate with the experimental findings. Ultimately, this suggests that the influence of the organic solvent on the solvation shell of the phosphate ions may not contribute significantly to the improved synthesis of CaP.

Reciprocal allosteric regulation, where binding events influence each other simultaneously, is a key target for supramolecular chemists designing biomimetic systems. Platinum(II) lantern-shaped cages, formed from a series of ligands bearing central protonatable sites of varied basicity through rational tuning of the backbone, featured nuanced dual action host-guest chemistry. This reveals the first example of reciprocal allostery in a supramolecular system, between protonation and anion binding. Switching studies were conducted using acid/base and silver/chloride stimuli, with single and multi-anion systems.

This paper presents a benchmarking study of DFT functionals and basis sets for the calculation of molecular geometries and binding energies of ion-solvent clusters. The systems examined include various monoatomic and polyatomic ions in water, methanol, and DMSO clusters. The use of high-quality triple-zeta basis sets is recommended for calculation of geometries though less-costly double-zeta basis set can often give good results due to systematic error cancellation. omega B97X-V and omega B97M-V are the two best-performing methods for single point energy calculation with mean errors well below the threshold of chemical accuracy (similar to 5 kJ mol(-1)) relative to DLPNO-CCSD(T)/CBS and revDSD-PBEP86-D4/def2-TZVPPD benchmarks.

Molecular properties in combined quantum mechanics and molecular mechanics (QM/MM) simulations have been shown to be dependent on the size of the quantum mechanical (QM) region and the amount of conformational sampling. Previous studies have largely focused on enzymatic systems, which have made it difficult to distinguish the effects of QM region size and conformational sampling from other factors including QM-MM boundary artifacts and the boundary effects. This study uses the difference-based adaptive solvation QM/MM method to investigate the tautomerization reactions of alanine and aspartate in explicit solvent. The choice of computationally tractable systems enables the decoupling of QM region size effects from other factors and a direct comparison of free energy surfaces with potential energy surfaces (PESs). The results show that (1) it is crucial to properly account for thermal fluctuations along the reaction pathways, and (2) free energy surfaces converge rapidly with increasing QM region size, whereas charge transfer requires a slightly larger QM region to achieve convergence. These findings are expected to guide future studies of enzymatic systems and other complex systems where QM/MM methods are applied.

Herein the morphology of aminomethylphosphonic acid (AMPA)-metal aggregates are analysed by ion mobility-mass spectrometry, DFT and IRMPD spectroscopy. Matching experimental collision cross section to the DFT predicted minima allowed unambiguous assignment of [M(AMPA)(AMPA-H)]+ where M = Mg2+, Ca2+, and Mn2+. Two distinct structural families of [M(AMPA)(AMPA-H)]+ where M = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Cu2+, and Zn2+ were differentiated by ion mobility mass spectrometry. Groupings of experimental collision cross sections were observed for a square pyramidal geometry, (M = Ca2+, Sr2+, Ba2+) versus a seesaw geometry (M = Mg2+, Mn2+, Cu2+, and Zn2+), paving the way for distinction of aggregates at the earliest stages of assembly.

Amphiphilicity is a key property that governs self-assembly, drug delivery and membrane permeability. We introduce a highly efficient approach based on polarisable continuum models to quantify this important property. Our modelling suggests that the accumulation of amphiphiles at the air-water interface is driven by the release of cavity formation energy in water.

A systematic series of QM cluster models has been developed to predict the trend in the carbonic anhydrase binding affinity of a structurally diverse dataset of ligands. Reference DLPNO-CCSD(T)/CBS binding energies were generated for a cluster model and used to evaluate the performance of contemporary density functional theory methods, including Grimme's "3c" DFT composite methods (r2SCAN-3c and omega B97X-3c). It is demonstrated that when validated QM methods are used, the predictive power of the cluster models improves systematically with the size of the cluster models. This provided valuable insights into the key interactions that need to be modeled quantum mechanically and could inform how the QM region should be defined in hybrid quantum mechanics/molecular mechanics (QM/MM) models. The use of r2SCAN-3c on the largest cluster model composed of 16 residues appears to be an economical approach to predicting binding trends compared with using more robust DFT methods such as omega B97M-V and provides a significant improvement compared with docking.

Perfluorooctanoic acid (PFOA) including linear and branched isomers is one of only three PFAS included in the Stockholm convention on Persistent Organic Pollutants. Unfortunately, PFOA branched isomers have received less attention than the linear due to analytical difficulties and perceived lower environmental concentrations. In this study, we revealed a environmentally relevant pathway for the formation of branched PFOA from PFAS precursors. AFFF samples showed a doubling of branched PFOA concentrations (138 mg/L) after TOP assay oxidation (307 mg/L). These findings indicate that branched PFOA may be more pervasive in the environment than previously thought. Additionally, we investigated the reductive degradability of PFOA using vitamin B12 (VB12) (a naturally occurring electron shuttle) in combination with either zero-valent zinc (ZVZ) or zero-valent iron (ZVI). Linear PFOA, as well as two branched isomers (3-methyl PFOA and 5,5-dimethyl PFOA), resisted reductive defluorination under the experimental conditions. However, all other branched isomers degraded within 10 days in the ZVZ-VB12 system. The experimental rate constants for specific PFOA isomers generally correlate with their calculated reduction potentials, except for 6-methyl PFOA. A potential defluorination pathway was proposed based on high-resolution mass spectrometry (LC-Orbitrap) and density functional theory (DFT) studies.

Recent work has highlighted how integration grid and self-interaction errors (SIE) can lead to divergent density functional many-body expansion. While the pernicious effect of basis set superposition error (BSSE) on many-body expansion has been known for some time, this effect is compounded by SIE and is likely to play an even more important role. In this study, we demonstrate that elimination of BSSE through the counterpoise correction can simultaneously attenuate sensitivity of MBE to DFT grid errors and reduce MBE errors by more than 50%. We focus on the same ion-water clusters examined in recent studies and further demonstrate that when effects of BSSE and DFT grid errors are minimized, charge embedding can be an effective strategy for mitigating SIE to restore the convergent behavior of many-body expansion.

Metalated glyphosate dimers were investigated by using electrospray ionization ion mobility-mass spectrometry and tandem ion mobility-infrared multiple photon dissociation-mass spectrometry. [M(glyphosate)(glyphosate-H)]+ dimers where M = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Cu2+ and Zn2+ were mass-selected prior to mobility separation. Each possessed a single mobility resolved isomer, with measured collision cross sections (N2CCSexp) ranging from 165 to 175 Å2. The dimers were all of similar size, with size trends consistent with periodic differences in the incorporated metals' cationic radii, except M = Cu2+. Upon IR irradiation between 2700 and 3700 cm-1, the experimental IR spectra of mass- and mobility-resolved [M(glyphosate)(glyphosate-H)]+ dimers revealed two significant absorption peaks at 3550 and 3660 cm-1. These correspond to the O-H stretching on both the carboxylate and phosphonate groups of the substituent glyphosate molecules. A thorough isomer search using CREST-CENSO algorithms and DFT optimization predicted the energetically preferred gas-phase structures of [M(glyphosate)(glyphosate-H)]+ dimers. Comparing calculated collision cross sections (N2CCScalc) and predicted vibrational frequencies with experimental data confirmed the predicted structures of the [M(glyphosate)(glyphosate-H)]+ dimers, which all share a common structural motif. In all cases, the incorporated deprotonated glyphosate is deprotonated at the phosphonate group. The divalent metal cation coordinates the deprotonated phosphonate group in a bidentate fashion and is located in the center of the dimer. The neutral glyphosate molecule is wrapped around the metal cation in an octahedral coordination. As the metal cation increases in size, the coordination distance increases, thereby increasing the overall size of the dimer. The different bonding afforded by M = Cu2+ to the amine nitrogen center leads to the observed structural difference for this metal, through the modulation of a key hydrogen bond in the dimer.

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.

Amphiphilicity is an important property for drug development and self-assembly. This paper introduces a general approach based on a simple fatty alcohol (dodecanol) membrane model that can be used to quantify the amphiphilicity of small molecules that are in good agreement with experimental surface tension data. By applying the model to a systematic series of compounds, it was possible to elucidate the effect of different motifs on amphiphilicity. The results further indicate that amphiphilicity correlates strongly with water-octanol partition coefficients (logP) for the 29 organic molecules examined in the 0 < logP < 4 range. Importantly, the simulation of the model membrane is an order of magnitude faster than a phospholipid membrane (e.g., 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) simulation and offers a simple atomistic approach for quantifying and predicting amphiphilicity of small drug-like molecules that could be used in quantitative structure-activity relationship studies.

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.

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.

Quinone compounds, with the ability to uptake protons, are promising electrodes for aqueous batteries. However, their applications are 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 lower the redox potentials of quinone materials. 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 one of 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 temperature.

Despite the success and widespread use of QM/MM methods in modeling (bio)chemically important processes, their accuracy is still not well understood. A key reason is because these methods are ultimately approximations to direct QM calculations of very large systems, which are impractical to perform in most cases. We highlight recent progress toward the development of realistic model systems where it is possible to obtain full QM reference data to directly and systematically evaluate the effectiveness of different QM/MM generation schemes. These model systems are highly flexible and can be tailored to probe the sensitivity of a QM/MM model to different reaction types and simulation parameters such as pairing of QM and MM potentials, QM region size, and composition. It is envisaged that this strategy could be used to directly validate different QM/MM generation schemes and spur the development of more robust models in the future.

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 PFAS accumulation in these products and the impact of these contaminants on milk protein function 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 β-lactoglobulin (β-LG). We observed that six of these PFAS bound to both protein isoforms with low to mid-micromolar dissociation constants. Based on competitive binding experiments with endogenous ligands, PFAS can bind orthosterically and preferentially to β-LG’s hydrophobic ligand-binding calyx. Interestingly, we also observed that β-cyclodextrin can suppress PFAS binding to β-LG, owing to the ability of β-cyclodextrin to directly sequester PFAS from solution. Together, this research sheds light on PFAS—β-LG binding, suggesting that such interactions could impact lipid/fatty acid transport in bovine mammary glands. Furthermore, our results highlight the potential use of β-cyclodextrin in mitigating PFAS binding, providing insights towards the development of strategies to reduce PFAS accumulation in dairy products and other biological systems.

A-value is conventionally defined as the ring flip Gibbs energy of chair conformers in monosubstituted cyclohexanes. It is well accepted in organic chemistry as one of the proxies of steric hindrance of a substituent group with respect to hydrogen. In this paper, the ring flip energy of mono– and dihalogenated cyclohexanes was investigated by high-level quantum chemical methods. Satisfactory agreements between calculated values and published experimental values from NMR were established before extending the concept to ring flip energies of polyhalogenated cyclohexanes. We assessed the qualitative and quantitative accuracy of prediction of ring flip energies by A-values in two models: a simple and intuitive model based on linear combinations of A-values and a proposed extension of this model to include geminal substituent interactions. The simple model results in poor predictions of ring flip energy in polyhalogenated cyclohexanes, and the extended model provides only slight improvement. Our data suggests that simple linear combination of traditional or extended A-values may not be appropriate for the energy prediction of systems in this study.

In the present study, we have examined the utility of counterpoise (CP) corrections, the zero-cost geometric counterpoise (gCP) correction, and the double-ζ vDZP basis set, in representative examples of computational chemistry investigations. The tests include reaction energies and barriers in mechanisms of catalysis, and binding of substrates with enzyme active sites. Drawbacks of the CP approach include: it is more costly than calculations with the same basis set without applying CP corrections, multiple computations may be required where a single species is used in multiple instances, and it is only applicable to intermolecular interactions. In comparison, using gCP or vDZP is less costly. Their overall accuracy is comparable to CP, although the three approaches show variable performances for different systems. Thus, the use of a large basis set remains more consistent in obtaining results that are closer to the basis-set limit. Where the computational cost poses a challenge, the use of gCP or vDZP would be more advantageous than CP in terms of cost and simplicity.