Protonation State Research Articles

Impact of the Unstirred Water Layer on the Permeation of Small-Molecule Drugs.

Over the last two decades, numerous molecular dynamics (MD) simulation-based investigations have attempted to predict the membrane permeability to small-molecule drugs as indicators of their bioavailability, a majority of which utilize the inhomogeneous solubility diffusion (ISD) model. However, MD-based membrane permeability is routinely 3-4 orders of magnitude larger than the values measured with the intestinal perfusion technique. There have been contentious discussions on the sources of the large discrepancies, and the two indisputable, potentially dominant ones are the fixed protonation state of the permeant and the neglect of the unstirred water layer (UWL). Employing six small-molecule drugs of different biopharmaceutical classification system classes, the current MD study relies on the ISD model but introduces the (de)protonation of the permeant by characterizing the permeation free energy of both neutral and charged states. In addition, the role of the UWL as a potential resistance against permeation is explored. The new MD protocol closely mimics the nature of small-molecule permeation and yields estimates that agree well with in vivo intestinal permeability.

Front Cover: Structural Changes to the Gd‐DTPA Complex at Varying Ligand Protonation State (Eur. J. Inorg. Chem. 6/2024)

Front Cover: Structural Changes to the Gd‐DTPA Complex at Varying Ligand Protonation State (Eur. J. Inorg. Chem. 6/2024)

Modeling pH-Dependent Biomolecular Photochemistry.

The tuning mechanism of pH can be extremely challenging to model computationally in complex biological systems, especially with respect to the photochemical properties. This article reports a protocol aimed at modeling pH-dependent photodynamics using a combination of constant-pH molecular dynamics and semiclassical nonadiabatic molecular dynamics simulations. With retinal photoisomerization in Anabaena sensory rhodopsin (ASR) as a testbed, we show that our protocol produces pH-dependent photochemical properties, such as the isomerization quantum yield or decay rates. We decompose our results into single-titrated residue contributions, identifying some key tuning amino acids. Additionally, we assess the validity of the single protonation state picture to represent the system at a given pH and propose the most populated protein charge state as a compromise between cost and accuracy.

Separation of protein corona from nanoparticles under intracellular acidic conditions: effect of protonation on nanoparticle-protein and protein-protein interactions.

Protein coronas separate from nanoparticles under intracellular acidic conditions however, competitive adsorption of multiple proteins and their protein network formation under different pH conditions have not yet been systematically studied at the atomic scale. Herein, we report all-atom molecular dynamics simulations of plasma proteins (human serum albumin and immunoglobulin gamma-1 chain C) adsorbed to 10 nm-sized carboxyl-terminated polystyrene (PS) nanoparticles at different protonation states that mimic extracellular and intracellular pH conditions of 7, 6-5, and 4.5. Binding free energies are calculated from umbrella sampling simulations, showing the significantly weakened binding between PS particles and proteins at the protonation state at pH 4.5, in agreement with experiments showing the separation of protein corona from nanoparticles at pH 4.5. Mixtures of multiple proteins and PS particles are also simulated, showing much less protein adsorption and protein cluster formation at the protonation state at pH 4.5 than that at higher pH values, which are further confirmed by calculating the diffusivities and hydrodynamic radii of individual proteins. In particular, electrostatic particle-protein and protein-protein interactions are significantly weakened by a combination of particle and protein protonation rather than by particle protonation alone, to an extent dependent on different proteins. These findings help explain the experimental observations regarding separation of protein corona from nanoparticles under intracellular acidic conditions at pH 4.5 but not at higher pH, supporting that acidification cannot be the only reason for this separation during the process of endosome maturation.

Universality of critical active site glutamate as an acid-base catalyst in serine hydroxymethyltransferase function.

Serine hydroxymethyltransferase (SHMT) is a key enzyme in the one-carbon metabolic pathway, utilizing the vitamin B6 derivative pyridoxal 5'-phosphate (PLP) and vitamin B9 derivative tetrahydrofolate (THF) coenzymes to produce essential biomolecules. Many types of cancer utilize SHMT in metabolic reprogramming, exposing the enzyme as a compelling target for antimetabolite chemotherapies. In pursuit of elucidating the catalytic mechanism of SHMT to aid in the design of SHMT-specific inhibitors, we have used room-temperature neutron crystallography to directly determine the protonation states in a model enzyme Thermus thermophilus SHMT (TthSHMT), which exhibits a conserved active site compared to human mitochondrial SHMT2 (hSHMT2). Here we report the analysis of TthSHMT, with PLP in the internal aldimine form and bound THF-analog, folinic acid (FA), by neutron crystallography to reveal H atom positions in the active site, including PLP and FA. We observed protonated catalytic Glu53 revealing its ability to change protonation state upon FA binding. Furthermore, we obtained X-ray structures of TthSHMT-Gly/FA, TthSHMT-l-Ser/FA, and hSHMT2-Gly/FA ternary complexes with the PLP-Gly or PLP-l-Ser external aldimines to analyze the active site configuration upon PLP reaction with an amino acid substrate and FA binding. Accurate mapping of the active site protonation states together with the structural information gained from the ternary complexes allow us to suggest an essential role of the gating loop conformational changes in the SHMT function and to propose Glu53 as the universal acid-base catalyst in both THF-independent and THF-dependent activities of SHMT.

Isoscalar giant resonances of <inline-formula><tex-math id="M1">\begin{document}$^{{\bf{18}}}_{{\boldsymbol{\Lambda\Lambda}}}{\bf{O}}$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M1.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M1.png"/></alternatives></inline-formula> in relativistic approach

The interactions between hyperon-nucleon and hyperon-hyperon have been an important topic in strangeness nuclear physics, which play an important role in understanding the properties of hypernuclei and equation of state of strangeness nuclear matter. It is very difficult to perform a direct scattering experiment of the nucleon and hyperon because the short lifetime of the hyperon. Therefore, the hyperon-nucleon interaction and the hyperon-hyperon interaction have been mainly investigated experimentally by <inline-formula><tex-math id="M4">\begin{document}$\gamma$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M4.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M4.png"/></alternatives></inline-formula> spectroscopy of single-<inline-formula><tex-math id="M5">\begin{document}$\Lambda$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M5.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M5.png"/></alternatives></inline-formula> hypernuclei or double-<inline-formula><tex-math id="M6">\begin{document}$\Lambda$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M6.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M6.png"/></alternatives></inline-formula> hypernuclei. There are also many theoretical methods developed to describe the properties of hypernuclei. Most of these models focus mostly on the ground state properties of hypernuclei, and have given exciting results in producing the banding energy, the energy of single-particle levels, deformations, and other properties of hypernuclei. Only a few researches adopting Skyrme energy density functionals is devoted to the study of the collective excitation properties of hypernuclei. In present work, we have extended the relativistic mean field and relativistic random phase approximation theories to study the collective excitation properties of hypernuclei, and use the methods to study the isoscalar collective excited state properties of double <inline-formula><tex-math id="M7">\begin{document}$\Lambda$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M7.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M7.png"/></alternatives></inline-formula> hypernuclei. First, the effect of <inline-formula><tex-math id="M8">\begin{document}$\Lambda$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M8.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M8.png"/></alternatives></inline-formula> hyperons on the single-particle energy of <sup>16</sup>O and <inline-formula><tex-math id="M9">\begin{document}$^{18}_{\Lambda\Lambda}{\rm{O}}$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M9.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M9.png"/></alternatives></inline-formula> are discussed in the relativistic mean field theory, the calculations are performed within TM1 parameter set and related hyperon-nucleon interaction, and hyperon-hyperon interaction. We find that it gives a larger attractive effect on the <inline-formula><tex-math id="M10">\begin{document}${{\mathrm{s}}}_{1/2}$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M10.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M10.png"/></alternatives></inline-formula> state of proton and neutron, while gives a weaker attractive effect on the state around Fermi surface. The self-consistent relativistic random phase approximation is used to study the collectively excited state properties of hypernucleus <inline-formula><tex-math id="M11">\begin{document}$^{18}_{\Lambda\Lambda}{\rm{O}}$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M11.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M11.png"/></alternatives></inline-formula>. The isoscalar giant monopole resonance and quadrupole resonance are calculated and analysed in detail, we pay more attention to the effect of the inclusion of <inline-formula><tex-math id="M12">\begin{document}$\Lambda$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M12.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M12.png"/></alternatives></inline-formula> hyperons on the properties of giant resonances. Comparing with the strength distributions of <sup>16</sup>O, changes of response function of <inline-formula><tex-math id="M13">\begin{document}$^{18}_{\Lambda\Lambda}{\rm{O}}$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M13.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M13.png"/></alternatives></inline-formula> are evidently found both on the isoscalar giant monopole resonance and quadrupole resonance. It is shown that the difference comes mainly from the change of Hartree energy of particle-hole configuration and the contribution of the excitations of <inline-formula><tex-math id="M14">\begin{document}$\Lambda$\end{document}</tex-math><alternatives><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M14.jpg"/><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="4-20231531_M14.png"/></alternatives></inline-formula> hyperons. We find that the hyperon-hyperon residual interactions have small effect on the monopole resonance function and quadrupole response function in the low-energy region, and have almost no effect on the response functions in the high-energy region.

Визначення водневого показника в точці нульового поверхневого заряду для гумінової кислоти бурого вугілля

Humic acids are a complex mixture of high molecular weight aromatic oxycarboxylic acids that act as polyelectrolytes. Their structure includes aromatic nuclei, side chains, and functional groups, resulting in a variation of physicochemical properties such as solubility and stability. Carboxylic and phenolic groups impart acidic properties, while amino groups cause amphotericity, which is related to the isoelectric point (pI). The amphiphilic character contributes to the formation of micelle-like structures in neutral and acidic environments. Humic acids form supramolecular colloids connected by hydrogen bonds. It is known that the pH at the zero charge point of different humic acids varies from 0.5 to 9.3, reflecting their chemical diversity. In our experiments humic acids were obtained by alkaline extraction from lignite with a carbon content of 40.5% and an ash content of 40%. The zero charge point (the pH at which a molecule carries no net electrical charge or is electrically neutral in the statistical mean) was determined by two methods using a pH titration procedure. These methods showed quite close pH values (2.0 and 1.6) at which the surface of humic acid has a net zero surface charge. This allows us to have information about the protonation state and charge dynamics of humic acid under different pH conditions. The data obtained helps to determine the solubility of the acid depending on the pH of the medium, which is important at the stage of acid precipitation in the process of its production, because of the zero charge point value can affect the solubility of a molecule at a given pH. Keywords: lignite, humic acids, composition, extraction, zero surface charge, pH indicator, acid-base titration. Corresponding author Savchenko V.V., e-mail: korbinity@gmail.com

H2 formation from the E2-E4 states of nitrogenase.

Nitrogenase is the only enzyme that can cleave the strong triple bond in N2, making nitrogen available for biological lifeforms. The active site is a MoFe7S9C cluster (the FeMo cluster) that binds eight electrons and protons during one catalytic cycle, giving rise to eight intermediate states E0-E7. It is experimentally known that N2 binds to the E4 state and that H2 is a compulsory byproduct of the reaction. However, formation of H2 is also an unproductive side reaction that should be avoided, especially in the early steps of the reaction mechanism (E2 and E3). Here, we study the formation of H2 for various structural interpretations of the E2-E4 states using combined quantum mechanical and molecular mechanical (QM/MM) calculations and four different density-functional theory methods. We find large differences in the predictions of the different methods. B3LYP strongly favours protonation of the central carbide ion and H2 cannot form from such structures. On the other hand, with TPSS, r2SCAN and TPSSh, H2 formation is strongly exothermic for all structures and En and therefore need strict kinetic control to be avoided. For the E2 state, the kinetic barriers for the low-energy structures are high enough to avoid H2 formation. However, for both the E3 and E4 states, all three methods predict that the best structure has two hydride ions bridging the same pair of Fe ions (Fe2 and Fe6) and these two ions can combine to form H2 with an activation barrier of only 29-57 kJ mol-1, corresponding to rates of 7 ×102 to 5 × 107 s-1, i.e. much faster than the turnover rate of the enzyme (1-5 s-1). We have also studied H-atom movements within the FeMo cluster, showing that the various protonation states can quite freely be interconverted (activation barriers of 12-69 kJ mol-1).

Sulfilimine bond formation in collagen IV.

The collagen IV network plays a crucial role in providing structural support and mechanical integrity to the basement membrane and surrounding tissues. A key aspect of this network is the formation of intra- and inter-collagen fibril crosslinks. One particular crosslink, an inter-residue sulfilimine bond, has been found, so far, to be unique to collagen IV. More specifically, these crosslinks are primarily formed between methionine and lysine or hydroxylysine residues and can occur within a single collagen fibril or between different collagen fibrils. Due to its significance as the major crosslink in the collagen IV network, the sulfilimine bond plays critical roles in tissue development and various human diseases. While the proposed reaction mechanism for sulfilimine bond formation is supported by experimental evidence, the precise nature of this bond remained uncertain until computational studies were conducted. The process involves the reaction of hypohalous acids (e.g., HOBr, HOCl), produced by a peroxidasin enzyme in the basement membrane, with the sidechain sulfur of methionine or sidechain nitrogen of lysine/hydroxylysine residues in collagen IV, to form halosulfonium or haloamine intermediates, respectively. The halosulfonium/haloamine then reacts with the sidechain amine/sulfide of the lysine (or hydroxylysine) or methionine respectively, eventually resulting in the formation of the sulfilimine (MetSNLys/Hyl) crosslink. The sulfilimine product formed not only plays a crucial role in physiological processes but also finds applications in various industrial and pharmaceutical contexts. In this review, we provide a comprehensive summary of existing studies, including our own research, aimed at understanding the reaction mechanism, protonation states, characteristic nature, and dynamic behavior of the sulfilimine bond in collagen IV. The goal is to offer readers an overview of this critically important biochemical bond.

Thiol Redox Proteomics for Identifying Redox-Sensitive Cysteine Residues Within the Protein of Interest During Stress.

Redox modulation is a common posttranslational modification to regulate protein activity. The targets of oxidizing agents are cysteine residues(Cys), which have to be exposed at the surface of the proteins and are characterized by an environment that favors redox modulation. This includes their protonation state and the neighboring amino acids. The Cys redox state can be assessed experimentally by redox titrations to determine the midpoint redox potential in the protein. Exposed cysteine residues and putative intramolecular disulfide bonds can be predicted by alignments with structural data using dedicated software tools and information on conserved cysteine residues. Labeling with light and heavy reagents, such as N-ethylmaleimide (NEM), followed by mass spectrometric analysis, allows for the experimental determination of redox-responsive cysteine residues. This type of thiol redox proteomics is a powerful approach to assessing the redox state of the cell, e.g., in dependence on environmental conditions and, in particular, under abiotic stress.

Phosphoester bond hydrolysis by a discrete zirconium-oxo cluster: mechanistic insights into the central role of the binuclear ZrIV-ZrIV active site.

Effective degradation of non-natural phosphate triesters (PTs) widely used in pesticides and warfare agents is of paramount relevance for human and environmental safety, particularly under acidic conditions where they are highly stable. Here, we present a detailed reactivity and mechanistic study pioneering discrete {Zr6O8} clusters, which are commonly employed as building blocks for Zr-MOFs and as non-classical soluble coordination compounds for the degradation of PTs using the pesticide ethyl paraoxon as a model. Combined computational studies, mechanistic experiments, and EXAFS analysis show that the reactivity of these clusters arises from their ZrIV-ZrIV bimetallic sites, which hydrolyze ethyl paraoxon under acidic conditions through an intramolecular pathway. Remarkably, the energetics of the reaction is dependent on the protonation state of the active sites, and a weakly acidic medium favors the reaction. Moreover, catalyst stability allowed for its recovery and reuse. Such a mechanism is in close analogy to enzymatic reactions and different from that previously reported for Zr-MOFs. These findings outline the potential of MIV-MIV active sites for PT degradation under challenging aqueous acidic conditions and contribute to the development of bioinspired catalysts and materials.

Measuring local pH at interfaces from molecular tumbling: A concept for designing EPR-active pH-sensitive labels and probes.

Molecular probes and indicators are broadly employed for pH measurements in bulk media and at interfaces. The underlying physical principle of pH measurements of most of these probes is based on a change in the electronic structure that, for example, results in a shift of the emission peak of the fluorescence probes, changes in NMR chemical shifts due to the affected electronic shielding, or magnetic parameters of pH-sensitive nitroxides as measured by EPR. Here we explore another concept for measuring local protonation state of molecular tags based on changes in rotational dynamics of electron spin-bearing moieties that are readily detected by conventional continuous wave X-band EPR. Such changes are especially pronounced at biological interfaces, such as lipid bilayer membranes, due to the probe interactions with adjacent charges and polarizable dipoles. The concept was demonstrated by synthesizing a series of pH-sensitive nitroxides and spin-labelled phospholipids. EPR spectra of these newly synthesized nitroxides exhibit relatively small - about 0.5 G - changes in isotropic nitrogen hyperfine coupling constant upon reversible protonation. However, spin-labelled phospholipids incorporated into lipid bilayers demonstrated almost 6-fold change in rotational correlation time upon protonation, readily allowing for pKa determination from large changes in EPR spectra. The demonstrated concept of EPR-based pH measurements leads to a broader range of potential nitroxide structures that can serve as molecular pH sensors at the desired pH range and, thus, facilitates further development of spin-labelling EPR methods to study electrostatic phenomena at chemical and biological interfaces.

Exploiting the full potential of cryo-EM maps

The Coulomb potential maps generated by electron microscopy (EM) experiments contain not only information about the position but also about the charge state of the atom. This feature of EM maps allows the identification of specific ions and the protonation state of amino acid side chains in the sample. Here, we summarize qualitative observations of charges in EM maps, discuss the difficulties in interpreting the charge in Coulomb potential maps with respect to distinguishing it from radiation damage, and outline considerations to implement the correct charge in fitting algorithms.

New model for aspartic acid species in aqueous calcium carbonate growth environments: challenges and perspectives.

The lack of experimental data on the dynamics of aspartic acid species in water for its range of protonation states and the details of their atomic-level interaction with aqueous calcium carbonate species is a driver for accurate force field development. A classical model that is consistent with the few pieces of experimental data available and with first principles calculations has been developed. The complex dynamics of the aspartate anions relevant to biomineralization and calcium carbonate crystal growth has been explored in water, providing a quantitative description of solvation structure and free energies, including conformational free energy profiles and pairing free energies. The model has been used to probe the structure and dynamics of aqueous calcium aspartate homo- and hetero-chiral clusters, confirming their unlikelihood due to weak and water-mediated interactions. This supports the hypothesis that the formation of such clusters, observed while growing vaterite in the presence of acidic chiral amino acids, is favoured by the presence of the crystal surface.

A new biphenol-dipicolylamine based ligand and its dinuclear Zn2+ complex as fluorescent sensors for ibuprofen and ketoprofen in aqueous solution.

In this work, the study of the new ligand 3,3'-bis[N,N-bis(pyridine-2-ylmethyl)aminomethyl]-2,2'-dihydroxybiphenyl (L) is reported, where a central 2,2'-biphenol (BPH) fluorophore was functionalized at 3,3'-positions with two dipicolylamine (DPA) side arms as receptor units. Following the synthesis and full chemical-physical characterization, the acid-base and Zn2+-coordination abilities of L were investigated through a combination of potentiometric, UV-Vis, fluorescence, NMR, XRD and DFT measurements. The optical properties of the ligand turned out to be strongly dependent on the pH, being straightforwardly associated with the protonation state of the BPH moiety, whereas its peculiar design allowed to form stable mono and dinuclear Zn2+ complexes. In the latter species, the presence of two Zn2+ ions coordinatively unsaturated and placed at close distance to each other, prompted us to test their usefulness as metallo-receptors for two environmental pollutants of great relevance, ibuprofen and ketoprofen. Potentiometric and fluorescence investigations evidenced that these important non-steroidal anti-inflammatory drugs (NSAIDs) are effectively coordinated by the metallo-receptors and, of relevance, both the stability and the fluorescence properties of the resulting ternary adducts are markedly affected by the different chemical architectures of the two substrates. This study aims at highlighting the promising perspectives arising from the use of polyamino phenolic ligands as chemosensors for H+/Zn2+ and other additional anionic targets in their metal-complexed forms.

An albumin unfolding and refolding cycle induced by a time-controlled pH jump.

Given the intimate connection between the structure and function of biological macromolecules, the ability to temporally control their unfolding-refolding process enables temporal regulation over specific functionalities, potentially applicable in innovative domains, including the construction of protein-based actuators or programmable catalysis and drug release in complex biotechnological processes. We show here how a temporally controlled protein unfolding-refolding cycle can be coupled in time with programmed pH sequences achieved through the spontaneous decomposition of an activated carboxylic acid. Specifically, we illustrate this process at the molecular level using albumin, the most prevalent protein found in plasma, for which a temporary shift from native to unfolded forms is promoted using nitroacetic acid, able to undergo base-catalysed decarboxylation when solubilized in water solution. As detected by small angle X-ray scattering and intrinsic tryptophan fluorescence, starting from the protein in its native form, the acid addition triggers unfolding to a partially denatured state and a subsequent time-tunable pH rise with gradual refolding that recapitulates the intermediate steps detected at the same pH values by static acidification, fitting within a framework of full reversibility of the structural changes as a function of the protein protonation state. At the end of the pH jump, the native structure is fully recovered, making this method a chemical tool to achieve a complete protein conformational sequence programmed in the timeframe of minutes without further intervention.

Electronic state modulation of Ag30 nanoclusters within a ring-shaped polyoxometalate.

Atomically precise Ag nanoclusters display distinctive properties that are dictated by their structures and electronic states. However, manipulating the electronic states of Ag nanoclusters is challenging owing to their inherent instability and susceptibility to undesired structural changes, decomposition, and aggregation. Recently, we reported the synthesis of a body-centered cubic {Ag30}22+ nanocluster encapsulated within a ring-shaped polyoxometalate (POM) [P8W48O184]40- by reacting 16 Ag+-containing [P8W48O184]40- with Ag+ using N,N-dimethylformamide (DMF) as a mild reducing agent. This led to a redox-induced structural transformation into a face-centered cubic {Ag30}16+ nanocluster. In this study, we demonstrated the modulation of the electronic states of Ag30 nanoclusters within the ring-shaped POM through two different approaches. A face-centered cubic {Ag30}18+ nanocluster, featuring distinct oxidation states compared to previously reported {Ag30}22+ and {Ag30}16+ nanoclusters, was synthesized using tetra-n-butylammonium borohydride, a stronger reducing agent than DMF, in the reaction of 16 Ag+-containing [P8W48O184]40- and Ag+. Additionally, by leveraging the acid-base properties of POMs, we demonstrated the reversible, stepwise modulation of the charge distribution in the Ag30 nanocluster through controlling protonation states of the ring-shaped POM ligand. These results highlight the potential of engineering POM-stabilized Ag nanoclusters with diverse structures and electronic states, thereby facilitating the exploration of novel properties and applications utilizing the unique characteristics of the POM ligands.

Structural descriptors and information extraction from X-ray emission spectra: aqueous sulfuric acid.

Machine learning can reveal new insights into X-ray spectroscopy of liquids when the local atomistic environment is presented to the model in a suitable way. Many unique structural descriptor families have been developed for this purpose. We benchmark the performance of six different descriptor families using a computational data set of 24 200 sulfur Kβ X-ray emission spectra of aqueous sulfuric acid simulated at six different concentrations. We train a feed-forward neural network to predict the spectra from the corresponding descriptor vectors and find that the local many-body tensor representation, smooth overlap of atomic positions and atom-centered symmetry functions excel in this comparison. We found a similar hierarchy when applying the emulator-based component analysis to identify and separate the spectrally relevant structural characteristics from the irrelevant ones. In this case, the spectra were dominantly dependent on the concentration of the system, whereas adding the second most significant degree of freedom in the decomposition allowed for distinction of the protonation state of the acid molecule.

Experimental and theoretical studies of pH-responsive iridium(III) complexes of azole and N-heterocyclic carbene ligands.

A series of nine luminescent iridium(III) complexes with pH-responsive imidazole and benzimidazole ligands have been prepared and characterized. The first series of complexes were of the form [Ir(ppy)2(N^N)]+ or [Ir(ppy)2(C^N)]+ (where ppy is 2-phenylpyridine and N^N is 2-(2-pyridyl)imidazole or 2-(2-pyridyl)benzimidazole and C^N represents a pyridyl-triazolylidene-based N-heterocyclic carbene ligand). For these complexes, the benzimidazole group was either unsubstituted or substituted with electron-withdrawing (Cl) or electron-donating (Me) groups. The second series of complexes were of the form [Ir(phbim)2(N^N)]+ or [Ir(phbim)2(C^N)]+ (where phbim is 2-phenylbenzimidazole and N^N is either 2,2'-bipyridine or 1,10-phenanthroline and C^N is either a pyridyl-imidazolylidene or pyridyl-triazolylidene N-heterocyclic carbene ligand). UV-visible and photoluminescence pH titration studies showed that changing the protonation state of these complexes results in significant changes in the photoluminescence emission properties. The pKa values of prepared complexes were estimated from the spectroscopic pH titration data and these values show that the nature of the pH-sensitive ligands (either main or ancillary ligands) resulted in a significant capacity to modulate the pKa values for these compounds with values ranging from 5.19-11.22. Theoretical investigations into the nature of the electronic transitions for the different protonation states of compounds were performed and the results were consistent with the experimental results.

Tuning Potential Functions to Host-Guest Binding Data.

Software to more rapidly and accurately predict protein-ligand binding affinities is of high interest for early-stage drug discovery, and physics-based methods are among the most widely used technologies for this purpose. The accuracy of these methods depends critically on the accuracy of the potential functions that they use. Potential functions are typically trained against a combination of quantum chemical and experimental data. However, although binding affinities are among the most important quantities to predict, experimental binding affinities have not to date been integrated into the experimental data set used to train potential functions. In recent years, the use of host-guest complexes as simple and tractable models of binding thermodynamics has gained popularity due to their small size and simplicity, relative to protein-ligand systems. Host-guest complexes can also avoid ambiguities that arise in protein-ligand systems such as uncertain protonation states. Thus, experimental host-guest binding data are an appealing additional data type to integrate into the experimental data set used to optimize potential functions. Here, we report the extension of the Open Force Field Evaluator framework to enable the systematic calculation of host-guest binding free energies and their gradients with respect to force field parameters, coupled with the curation of 126 host-guest complexes with available experimental binding free energies. As an initial application of this novel infrastructure, we optimized generalized Born (GB) cavity radii for the OBC2 GB implicit solvent model against experimental data for 36 host-guest systems. This refitting led to a dramatic improvement in accuracy for both the training set and a separate test set with 90 additional host-guest systems. The optimized radii also showed encouraging transferability from host-guest systems to 59 protein-ligand systems. However, the new radii are significantly smaller than the baseline radii and lead to excessively favorable hydration free energies (HFEs). Thus, users of the OBC2 GB model currently may choose between GB cavity radii that yield more accurate binding affinities and GB cavity radii that yield more accurate HFEs. We suspect that achieving good accuracy on both will require more far-reaching adjustments to the GB model. We note that binding free-energy calculations using the OBC2 model in OpenMM gain about a 10× speedup relative to corresponding explicit solvent calculations, suggesting a future role for implicit solvent absolute binding free-energy (ABFE) calculations in virtual compound screening. This study proves the principle of using host-guest systems to train potential functions that are transferrable to protein-ligand systems and provides an infrastructure that enables a range of applications.