Multipolar Atom Types from Theory and Statistical Clustering (MATTS) Data Bank: Impact of Surrounding Atoms on Electron Density from Cluster Analysis.

The multipole model (MM) uses an aspherical approach to describe electron density and can be used to interpret data from X-ray diffraction in a more accurate manner than using the spherical approximation. The MATTS (multipolar atom types from theory and statistical clustering) data bank gathers MM parameters specific for atom types in proteins, nucleic acids, and organic molecules. However, it was not fully understood how the electron density of particular atoms responds to their surroundings and which factors describe the electron density in molecules within the MM. In this work, by applying clustering using descriptors available in the MATTS data bank, that is, topology and multipole parameters, we found the topology features with the biggest impact on the multipole parameters: the element of the central atom, the number of first neighbors, and planarity of the group. The similarities in the spatial distribution of electron density between and within atom type classes revealed distinct and unique atom types. The quality of existing types can be improved by adding better parametrization, definitions, and local coordinate systems. Future development of the MATTS data bank should lead to a wider range of atom types necessary to construct the electron density of any molecule.

Multipolar Atom Types from Theory and Statistical Clustering (MATTS) Data Bank: Restructurization and Extension of UBDB.

A fast and accurate operational model of electron density is crucial in many scientific disciplines including crystallography, molecular biology, pharmaceutical, and structural chemistry. In quantum crystallography, the aspherical refinement of crystal structures is becoming increasingly popular because of its accurate description in terms of physically meaningful properties. The transferable aspherical atom model (TAAM) is quick and precise, though it requires a robust algorithm for atom typing and coverage of the most popular atom types present in small organic molecules. Thus, the University at Buffalo Databank (UBDB) has been renamed to the Multipolar Atom Types from Theory and Statistical clustering (MATTS) data bank, broadened, restructured, and implemented into the software DiSCaMB with 651 atom types obtained from 2316 small-molecule crystal structures containing C, H, N, O, P, S, F, Cl, and Br atoms. MATTS2021 data bank now covers most of the small molecules, peptides, RNA, DNA, and some frequently occurring cations and anions in biological, pharmaceutical, and organic materials, including the majority of known crystal structures composed of the above elements. The multipole model parameters (Pval, κ, κ', Plm) obtained for different atom types were greatly influenced by neighboring atom types, hybridization, geometrical strain in the ring system, and charges on the molecule. Contrary to previous findings, the atoms showing variable oxidation states and ions deviate from the linear dependence of monopole-derived charges on the expansion-contraction κ parameter.

Frequency and hydrogen bonding of nucleobase homopairs in small molecule crystals.

We used the high resolution and accuracy of the Cambridge Structural Database (CSD) to provide detailed information regarding base pairing interactions of selected nucleobases. We searched for base pairs in which nucleobases interact with each other through two or more hydrogen bonds and form more or less planar structures. The investigated compounds were either free forms or derivatives of adenine, guanine, hypoxanthine, thymine, uracil and cytosine. We divided our findings into categories including types of pairs, protonation patterns and whether they are formed by free bases or substituted ones. We found base pair types that are exclusive to small molecule crystal structures, some that can be found only in RNA containing crystal structures and many that are native to both environments. With a few exceptions, nucleobase protonation generally followed a standard pattern governed by pKa values. The lengths of hydrogen bonds did not depend on whether the nucleobases forming a base pair were charged or not. The reasons why particular nucleobases formed base pairs in a certain way varied significantly.

Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease.

Computational analysis of protein-ligand interactions is of crucial importance for drug discovery. Assessment of ligand binding energy allows us to have a glimpse of the potential of a small organic molecule to be a ligand to the binding site of a protein target. Available scoring functions, such as in docking programs, all rely on equations that sum each type of protein-ligand interactions in order to predict the binding affinity. Most of the scoring functions consider electrostatic interactions involving the protein and the ligand. Electrostatic interactions constitute one of the most important part of total interactions between macromolecules. Unlike dispersion forces, they are highly directional and therefore dominate the nature of molecular packing in crystals and in biological complexes and contribute significantly to differences in inhibition strength among related enzyme inhibitors. In this study, complexes of HIV-1 protease with inhibitor molecules (JE-2147 and darunavir) were analyzed by using charge densities from the transferable aspherical-atom University at Buffalo Databank (UBDB). Moreover, we analyzed the electrostatic interaction energy for an ensemble of structures, using molecular dynamic simulations to highlight the main features of electrostatic interactions important for binding affinity.

Dynamical refinement with multipolar electron scattering factors.

Dynamical refinement is a well established method for refining crystal structures against 3D electron diffraction (ED) data and its benefits have been discussed in the literature [Palatinus, Petrícek & Corrêa, (2015). Acta Cryst. A71, 235-244; Palatinus, Corrêa et al. (2015). Acta Cryst. B71, 740-751]. However, until now, dynamical refinements have only been conducted using the independent atom model (IAM). Recent research has shown that a more accurate description can be achieved by applying the transferable aspherical atom model (TAAM), but this has been limited only to kinematical refinements [Gruza et al. (2020). Acta Cryst. A76, 92-109; Jha et al. (2021). J. Appl. Cryst. 54, 1234-1243]. In this study, we combine dynamical refinement with TAAM for the crystal structure of 1-methyluracil, using data from precession ED. Our results show that this approach improves the residual Fourier electrostatic potential and refinement figures of merit. Furthermore, it leads to systematic changes in the atomic displacement parameters of all atoms and the positions of hydrogen atoms. We found that the refinement results are sensitive to the parameters used in the TAAM modelling process. Though our results show that TAAM offers superior performance compared with IAM in all cases, they also show that TAAM parameters obtained by periodic DFT calculations on the refined structure are superior to the TAAM parameters from the UBDB/MATTS database. It appears that multipolar parameters transferred from the database may not be sufficiently accurate to provide a satisfactory description of all details of the electrostatic potential probed by the 3D ED experiment.

On the structure refinement of metal complexes against 3D electron diffraction data using multipolar scattering factors.

This study examines various methods for modelling the electron density and, thus, the electrostatic potential of an organometallic complex for use in crystal structure refinement against 3D electron diffraction (ED) data. It focuses on modelling the scattering factors of iron(III), considering the electron density distribution specific for coordination with organic linkers. We refined the structural model of the metal-organic complex, iron(III) acetylacetonate (FeAcAc), using both the independent atom model (IAM) and the transferable aspherical atom model (TAAM). TAAM refinement initially employed multipolar parameters from the MATTS databank for acetylacetonate, while iron was modelled with a spherical and neutral approach (TAAM ligand). Later, custom-made TAAM scattering factors for Fe-O coordination were derived from DFT calculations [TAAM-ligand-Fe(III)]. Our findings show that, in this compound, the TAAM scattering factor corresponding to Fe3+ has a lower scattering amplitude than the Fe3+ charged scattering factor described by IAM. When using scattering factors corresponding to the oxidation state of iron, IAM inaccurately represents electrostatic potential maps and overestimates the scattering potential of the iron. In addition, TAAM significantly improved the fitting of the model to the data, shown by improved R1 values, goodness-of-fit (GooF) and reduced noise in the Fourier difference map (based on the residual distribution analysis). For 3D ED, R1 values improved from 19.36% (IAM) to 17.44% (TAAM-ligand) and 17.49% (TAAM-ligand-Fe3+), and for single-crystal X-ray diffraction (SCXRD) from 3.82 to 2.03% and 1.98%, respectively. For 3D ED, the most significant R1 reductions occurred in the low-resolution region (8.65-2.00 Å), dropping from 20.19% (IAM) to 14.67% and 14.89% for TAAM-ligand and TAAM-ligand-Fe(III), respectively, with less improvement in high-resolution ranges (2.00-0.85 Å). This indicates that the major enhancements are due to better scattering modelling in low-resolution zones. Furthermore, when using TAAM instead of IAM, there was a noticeable improvement in the shape of the thermal ellipsoids, which more closely resembled those of an SCXRD-refined model. This study demonstrates the applicability of more sophisticated scattering factors to improve the refinement of metal-organic complexes against 3D ED data, suggesting the need for more accurate modelling methods and highlighting the potential of TAAM in examining the charge distribution of large molecular structures using 3D ED.

TAAM refinement on high-resolution experimental and simulated 3D ED/MicroED data for organic molecules.

3D electron diffraction (3D ED), or microcrystal electron diffraction (MicroED), has become an alternative technique for determining the high-resolution crystal structures of compounds from sub-micron-sized crystals. Here, we considered L-alanine, α-glycine and urea, which are known to form good-quality crystals, and collected high-resolution 3D ED data on our in-house TEM instrument. In this study, we present a comparison of independent atom model (IAM) and transferable aspherical atom model (TAAM) kinematical refinement against experimental and simulated data. TAAM refinement on both experimental and simulated data clearly improves the model fitting statistics (R factors and residual electrostatic potential) compared to IAM refinement. This shows that TAAM better represents the experimental electrostatic potential of organic crystals than IAM. Furthermore, we compared the geometrical parameters and atomic displacement parameters (ADPs) resulting from the experimental refinements with the simulated refinements, with the periodic density functional theory (DFT) calculations and with published X-ray and neutron crystal structures. The TAAM refinements on the 3D ED data did not improve the accuracy of the bond lengths between the non-H atoms. The experimental 3D ED data provided more accurate H-atom positions than the IAM refinements on the X-ray diffraction data. The IAM refinements against 3D ED data had a tendency to lead to slightly longer X-H bond lengths than TAAM, but the difference was statistically insignificant. Atomic displacement parameters were too large by tens of percent for L-alanine and α-glycine. Most probably, other unmodelled effects were causing this behaviour, such as radiation damage or dynamical scattering.

Hirshfeld atom refinement and dynamical refinement of hexagonal ice structure from electron diffraction data.

Reaching beyond the commonly used spherical atomic electron density model allows one to greatly improve the accuracy of hydrogen atom structural parameters derived from X-ray data. However, the effects of atomic asphericity are less explored for electron diffraction data. In this work, Hirshfeld atom refinement (HAR), a method that uses an accurate description of electron density by quantum mechanical calculation for a system of interest, was applied for the first time to the kinematical refinement of electron diffraction data. This approach was applied here to derive the structure of ordinary hexagonal ice (Ih). The effect of introducing HAR is much less noticeable than in the case of X-ray refinement and it is largely overshadowed by dynamical scattering effects. It led to only a slight change in the O-H bond lengths (shortening by 0.01 Å) compared with the independent atom model (IAM). The average absolute differences in O-H bond lengths between the kinematical refinements and the reference neutron structure were much larger: 0.044 for IAM and 0.046 Šfor HAR. The refinement results changed considerably when dynamical scattering effects were modelled - with extinction correction or with dynamical refinement. The latter led to an improvement of the O-H bond length accuracy to 0.021 Šon average (with IAM refinement). Though there is a potential for deriving more accurate structures using HAR for electron diffraction, modelling of dynamical scattering effects seems to be a necessary step to achieve this. However, at present there is no software to support both HAR and dynamical refinement.

Evaluating the Neuroprotective Potential of Novel Benzodioxole Derivatives in Parkinson's Disease via AMPA Receptor Modulation.

Parkinson's disease (PD) is a significant health issue because it gradually damages the nervous system. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors play a significant role in the development of PD. The current investigation employed hybrid benzodioxole-propanamide (BDZ-P) compounds to get information on AMPA receptors, analyze their biochemical and biophysical properties, and assess their neuroprotective effects. Examining the biophysical characteristics of all the subunits of the AMPA receptor offers insights into the impact of BDZ-P on the desensitization and deactivation rate. It demonstrates a partial improvement in the locomotor capacities in a mouse model of Parkinson's disease. In addition, the in vivo experiment assessed the locomotor activity by utilizing the open-field test. Our findings demonstrated that BDZ-P7 stands out with its remarkable potency, inhibiting the GluA2 subunit nearly 8-fold with an IC50 of 3.03 µM, GluA1/2 by 7.5-fold with an IC50 of 3.14 µM, GluA2/3 by nearly 7-fold with an IC50 of 3.19 µM, and GluA1 by 6.5-fold with an IC50 of 3.2 µM, significantly impacting the desensitization and deactivation rate of the AMPA receptor. BDZ-P7 showed an in vivo impact of partially reinstating locomotor abilities in a mouse model of PD. The results above suggest that the BDZ-P7 compounds show great promise as top contenders for the development of novel neuroprotective therapies.

Exploration of isoxazole analogs: Synthesis, COX inhibition, anticancer screening, 3D multicellular tumor spheroids, and molecular modeling.

In this study, a new series of Isoxazole-carboxamide derivatives were synthesized and characterized via HRMS, 1H-, 13CAPT-NMR, and MicroED. The findings revealed that nearly all of the synthesized derivatives exhibited potent inhibitory activities against both COX enzymes, with IC50 values ranging from 4.1 nM to 3.87 µM. Specifically, MYM1 demonstrated the highest efficacy among the compounds tested against the COX-1, displaying an IC50 value of 4.1 nM. The results showed that 5 compounds possess high COX-2 isozyme inhibitory effects with IC50 value in range 0.24-1.30 µM with COX-2 selectivity indexes (2.51-6.13), among these compounds MYM4 has the lowest IC50 value against COX-2, with selectivity index around 4. Intriguingly, this compound displayed significant antiproliferative effects against CaCo-2, Hep3B, and HeLa cancer cell lines, with IC50 values of 10.22, 4.84, and 1.57 µM, respectively, which was nearly comparable to that of doxorubicin. Compound MYM4 showed low cytotoxic activities on normal cell lines LX-2 and Hek293t with IC50 values 20.01 and 216.97 µM respectively, with safer values than doxorubicin. Furthermore, compound MYM4 was able to induce the apoptosis, suppress the colonization of both HeLa and HepG2 cells. Additionally, the induction of Reactive oxygen species (ROS) production could be the mechanism underlying the apoptotic effect and the cytotoxic activity of the compound. In the 3D multicellular tumor spheroid model, results revealed that MYM4 compound hampered the spheroid formation capacity of Hep3B and HeLa cancer cells. Moreover, the molecular docking of MYM4 compound revealed a high affinity for the COX2 enzyme, with energy scores (S) -7.45 kcal/mol, which were comparable to celecoxib (S) -8.40 kcal/mol. Collectively, these findings position MYM4 as a promising pharmacological candidate as COX inhibitor and anticancer agent.

Aspherical atom refinements on X-ray data of diverse structures including disordered and covalent organic framework systems: a time-accuracy trade-off.

Aspherical atom refinement is the key to achieving accurate structure models, displacement parameters, hydrogen-bond lengths and analysis of weak interactions, amongst other examples. There are various quantum crystallographic methods to perform aspherical atom refinement, including Hirshfeld atom refinement (HAR) and transferable aspherical atom model (TAAM) refinement. Both HAR and TAAM have their limitations and advantages, the former being more accurate and the latter being faster. With the advent of non-spherical atoms in Olex2 (NoSpherA2), it is now possible to overcome some limitations, like treating disorder, twinning and network structures, in aspherical refinements using HAR, TAAM or both together. TAAM refinement in NoSpherA2 showed significant improvement in refinement statistics compared with independent atom model (IAM) refinements on a diverse set of X-ray diffraction data. The sensitivity of TAAM towards poor data quality and disorder was observed in terms of higher refinement statistics for such structures. A comparison of IAM with TAAM and HAR in NoSpherA2 indicated that the time taken by TAAM refinements was of the same order of magnitude as that taken by IAM, while in HAR the time taken using a minimal basis set was 50 times higher than for IAM and rapidly increased with increasing size of the basis sets used. The displacement parameters for hydrogen and non-hydrogen atoms were very similar in both HAR and TAAM refinements. The hydrogen-bond lengths were slightly closer to neutron reference values in the case of HAR with higher basis sets than in TAAM. To benefit from the advantages of each method, a new hybrid refinement approach has been introduced, allowing a combination of IAM, HAR and TAAM in one structure refinement. Refinement of coordination complexes involving metal-organic compounds and network structures such as covalent organic frameworks and metal-organic frameworks is now possible in a hybrid mode such as IAM-TAAM or HAR-TAAM, where the metal atoms are treated via either the IAM or HAR method and the organic part via TAAM, thus reducing the computational costs without compromising the accuracy. Formal charges on the metal and ligand can also be introduced in hybrid-mode refinement.

Characterization and Investigation of Novel Benzodioxol Derivatives as Antidiabetic Agents: An In Vitro and In Vivo Study in an Animal Model.

In this study, we synthesized benzodioxol carboxamide derivatives and investigated their antidiabetic potential. The synthesized compounds (Ia-Ic and IIa-IId) underwent characterization via HRMS, 1H-, 13CAPT-NMR, and MicroED. Their efficacy against α-amylase was assessed in vitro, while MTS assays were employed to gauge cytotoxicity across cancer and normal cell lines. Additionally, the antidiabetic impact of compound IIc was evaluated in vivo using a streptozotocin-induced diabetic mice model. Notably, IIa and IIc displayed potent α-amylase inhibition (IC50 values of 0.85 and 0.68 µM, respectively) while exhibiting a negligible effect on the Hek293t normal cell line (IC50 > 150 µM), suggesting their safety. Compound IId demonstrated significant activity against four cancer cell lines (26-65 µM). In vivo experiments revealed that five doses of IIc substantially reduced mice blood glucose levels from 252.2 mg/dL to 173.8 mg/dL in contrast to the control group. The compelling in vitro anticancer efficacy of IIc and its safety for normal cells underscores the need for further in vivo assessment of this promising compound. This research highlights the potential of benzodioxol derivatives as candidates for the future development of synthetic antidiabetic drugs.

Theoretical 3D electron diffraction electrostatic potential maps of proteins modeled with a multipolar pseudoatom data bank.

The availability of atomic resolution experimental maps of electrostatic potential from 3D electron diffraction (3D ED) extends the possibility of investigating the electrostatic potential beyond the determination of non-H-atom positions. However, accurate tools to calculate this potential for macromolecules, without the use of expensive quantum calculations, are lacking. The University at Buffalo Data Bank (UBDB) gathers atom types that can be used to calculate accurate electrostatic potential maps via structure-factor calculations. Here, the transferable aspherical atom model (TAAM) is applied with UBDB to investigate theoretically obtained electrostatic potential maps of lysozyme and proteinase K, and compare them with experimental maps from 3D ED. UBDB better reproduces the molecular electrostatic potential of molecules within their entire volume compared with the neutral spherical models used in the popular independent atom model (IAM). Additionally, the theoretical electron-density maps of the studied proteins are shown and compared with the electrostatic potential maps. The atomic displacement parameters (B factors) may affect the electrostatic potential maps in a different way than in the case of electron-density maps. The computational method presented in this study could potentially facilitate the interpretation of the less resolved regions of cryo-electron microscopy density maps and pave the way for distinguishing between different ions/water molecules in the active sites of macromolecules in high-resolution structures, which is of interest for drug-design purposes.

The Role of Electrostatic Interactions in IFIT5-RNA Complexes Predicted by the UBDB+EPMM Method.

Electrostatic energy has a significant contribution to intermolecular interaction energy, especially in biological systems. Unfortunately, precise quantum mechanics calculations are not feasible for large biological systems; hence, simpler calculation methods are required. We propose a method called UBDB+EPMM (University at Buffalo Pseudoatom DataBank + Exact Potential Multipole Moments), which shortens computational time without losing accuracy. Here, we characterize electrostatic interactions in selected complexes of IFIT proteins with RNA. IFIT proteins are effectors of the innate immune system, and by binding foreign RNA, they prevent the synthesis of viral proteins in human host cells; hence, they block the propagation of viruses. We show that by using the UBDB+EPMM method it is possible to describe protein-RNA interactions not only qualitatively but also quantitatively. Looking at the charge penetration contribution to electrostatic interactions, we find all amino acid residues with strong local interactions. Moreover, we confirm that electrostatic interaction of IFIT5 with pppRNA does not depend on the sequence of the RNA.

Refinement of organic crystal structures with multipolar electron scattering factors.

A revolution in resolution is occurring now in electron microscopy arising from the development of methods for imaging single particles at cryogenic temperatures and obtaining electron diffraction data from nanocrystals of small organic molecules or macromolecules. Near-atomic or even atomic resolution of molecular structures can be achieved. The basis of these methods is the scattering of an electron beam due to the electrostatic potential of the sample. To analyse these high-quality experimental data, it is necessary to use appropriate atomic scattering factors. The independent atom model (IAM) is commonly used although various more advanced models, already known from X-ray diffraction, can also be applied to enhance the analysis. In this study a comparison is presented of IAM and TAAM (transferable aspherical atom model), the latter with the parameters of the Hansen-Coppens multipole model transferred from the University at Buffalo Databank (UBDB). By this method, TAAM takes into account the fact that atoms in molecules are partially charged and are not spherical. Structure refinements were performed on a carbamazepine crystal using electron structure-factor amplitudes determined experimentally [Jones et al. (2018). ACS Cent. Sci. 4, 1587-1592] or modelled with theoretical quantum-mechanical methods. The results show the possibilities and limitations of the TAAM method when applied to electron diffraction. Among others, the method clearly improves model fitting statistics, when compared with IAM, and allows for reliable refinement of atomic thermal parameters. The improvements are more pronounced with poorer-resolution diffraction data.

TAAM: a reliable and user friendly tool for hydrogen-atom location using routine X-ray diffraction data.

Hydrogen is present in almost all of the molecules in living things. It is very reactive and forms bonds with most of the elements, terminating their valences and enhancing their chemistry. X-ray diffraction is the most common method for structure determination. It depends on scattering of X-rays from electron density, which means the single electron of hydrogen is difficult to detect. Generally, neutron diffraction data are used to determine the accurate position of hydrogen atoms. However, the requirement for good quality single crystals, costly maintenance and the limited number of neutron diffraction facilities means that these kind of results are rarely available. Here it is shown that the use of Transferable Aspherical Atom Model (TAAM) instead of Independent Atom Model (IAM) in routine structure refinement with X-ray data is another possible solution which largely improves the precision and accuracy of X-H bond lengths and makes them comparable to averaged neutron bond lengths. TAAM, built from a pseudoatom databank, was used to determine the X-H bond lengths on 75 data sets for organic molecule crystals. TAAM parametrizations available in the modified University of Buffalo Databank (UBDB) of pseudoatoms applied through the DiSCaMB software library were used. The averaged bond lengths determined by TAAM refinements with X-ray diffraction data of atomic resolution (dmin ≤ 0.83 Å) showed very good agreement with neutron data, mostly within one single sample standard deviation, much like Hirshfeld atom refinement (HAR). Atomic displacements for both hydrogen and non-hydrogen atoms obtained from the refinements systematically differed from IAM results. Overall TAAM gave better fits to experimental data of standard resolution compared to IAM. The research was accompanied with development of software aimed at providing user-friendly tools to use aspherical atom models in refinement of organic molecules at speeds comparable to routine refinements based on spherical atom model.

Extension of the transferable aspherical pseudoatom data bank for the comparison of molecular electrostatic potentials in structure-activity studies.

The transferable aspherical pseudoatom data bank, UBDB2018, is extended with over 130 new atom types present in small and biological molecules of great importance in biology and chemistry. UBDB2018 can be applied either as a source of aspherical atomic scattering factors in a standard X-ray experiment (dmin ≃ 0.8 Å) instead of the independent atom model (IAM), and can therefore enhance the final crystal structure geometry and refinement parameters; or as a tool to reconstruct the molecular charge-density distribution and derive the electrostatic properties of chemical systems for which 3D structural data are available. The extended data bank has been extensively tested, with the focus being on the accuracy of the molecular electrostatic potential computed for important drug-like molecules, namely the HIV-1 protease inhibitors. The UBDB allows the reconstruction of the reference B3LYP/6-31G** potentials, with a root-mean-squared error of 0.015 e bohr-1 computed for entire potential grids which span values from ca 200 e bohr-1 to ca -0.1 e bohr-1 and encompass both the inside and outside regions of a molecule. UBDB2018 is shown to be applicable to enhancing the physical meaning of the molecular electrostatic potential descriptors used to construct predictive quantitative structure-activity relationship/quantitative structure-property relationship (QSAR/QSPR) models for drug discovery studies. In addition, it is suggested that electron structure factors computed from UBDB2018 may significantly improve the interpretation of electrostatic potential maps measured experimentally by means of electron diffraction or single-particle cryo-EM methods.

Differences and similarities among hypoxanthinium nitrate hydrate structures.

Crystals of hypoxanthinium (6-oxo-1H,7H-purin-9-ium) nitrate hydrates were investigated by means of X-ray diffraction at different temperatures. The data for hypoxanthinium nitrate monohydrate (C5H5N4O+·NO3-·H2O, Hx1) were collected at 20, 105 and 285 K. The room-temperature phase was reported previously [Schmalle et al. (1990). Acta Cryst. C46, 340-342] and the low-temperature phase has not been investigated yet. The structure underwent a phase transition, which resulted in a change of space group from Pmnb to P21/n at lower temperature and subsequently in nonmerohedral twinning. The structure of hypoxanthinium dinitrate trihydrate (H3O+·C5H5N4O+·2NO3-·2H2O, Hx2) was determined at 20 and 100 K, and also has not been reported previously. The Hx2 structure consists of two types of layers: the `hypoxanthinium nitrate monohydrate' layers (HX) observed in Hx1 and layers of Zundel complex H3O+·H2O interacting with nitrate anions (OX). The crystal can be considered as a solid solution of two salts, i.e. hypoxanthinium nitrate monohydrate, C5H5N4O+·NO3-·H2O, and oxonium nitrate monohydrate, H3O+(H2O)·NO3-.

Molecular tapes in the structure of isoguaninium chloride.

Isoguanine, an analogue of guanine, is of intrinsic interest as a noncanonical nucleobase. The crystal structure of isoguaninium chloride (systematic name: 6-amino-2-oxo-1H,7H-purin-3-ium chloride), C5H6N5O+·Cl-, has been determined by single-crystal X-ray diffraction. Structure analysis was supported by electrostatic interaction energy (Ees) calculations based on charge density reconstructed with the UBDB databank. In the structure, two kinds of molecular tapes are observed, one parallel to (010) and the other parallel to (50-4). The tapes are formed by dimers of isoguaninium cations interacting with chloride anions. Ees analysis indicates that cations in one kind of tape are oriented so as to minimize repulsive electrostatic interactions.

Protonated nucleobases are not fully ionized in their chloride salt crystals and form metastable base pairs further stabilized by the surrounding anions.

This paper presents experimental charge-density studies of cytosinium chloride, adeninium chloride hemihydrate and guaninium dichloride crystals based on ultra-high-resolution X-ray diffraction data and extensive theoretical calculations. The results confirm that the cohesive energies of the studied systems are dominated by contributions from intermolecular electrostatic interactions, as expected for ionic crystals. Electrostatic interaction energies (Ees) usually constitute 95% of the total interaction energy. The Ees energies in this study were several times larger in absolute value when compared, for example, with dimers of neutral nucleobases. However, they were not as large as some theoretical calculations have predicted. This was because the molecules appeared not to be fully ionized in the studied crystals. Apart from charge transfer from chlorine to the protonated nucleobases, small but visible charge redistribution within the nucleobase cations was observed. Some dimers of singly protonated bases in the studied crystals, namely a cytosinium-cytosinium trans sugar/sugar edge pair and an adeninium-adeninium trans Hoogsteen/Hoogsteen edge pair, exhibited attractive interactions (negative values of Ees) or unusually low repulsion despite identical molecular charges. The pairs are metastable as a result of strong hydrogen bonding between bases which overcompensates the overall cation-cation repulsion, the latter being weakened due to charge transfer and molecular charge-density polarization.