Enhancing hydrogen positions in X-ray structures of transition metal hydride complexes with dynamic quantum crystallography.

Hirshfeld atom refinement (HAR) is a method which enables the user to obtain more accurate positions of hydrogen atoms bonded to light chemical elements using X-ray data. When data quality permits, this method can be extended to hydrogen-bonded transition metals (TMs), as in hydride complexes. However, addressing hydrogen thermal motions with HAR, particularly in TM hydrides, presents a challenge. At the same time, proper description of thermal vibrations can be vital for determining hydrogen positions correctly. In this study, we employ tools such as SHADE3 and Normal Mode Refinement (NoMoRe) to estimate anisotropic displacement parameters (ADPs) for hydrogen atoms during HAR and IAM refinements performed for seven structures of TM (Fe, Ni, Cr, Nb, Rh and Os) and metalloid (Sb) hydride complexes for which both the neutron and the X-ray structures have been determined. A direct comparison between neutron and HAR/SHADE3/NoMoRe ADPs reveals that the similarity between neutron hydrogen ADPs and those estimated with NoMoRe or SHADE3 is significantly higher than when hydrogen ADPs are refined with HAR. Regarding TM-H bond lengths, traditional HAR exhibits a slight advantage over the other methods. However, combining NoMoRe/SHADE3 with HAR results in a minor decrease in agreement with neutron TM-H bond lengths. For the Cr complex, for which high-resolution X-ray data were collected, an investigation of resolution-related effects was possible.

Hirshfeld atom refinement of metal-organic frameworks for accurate positioning of hydrogen atoms and disorder analysis.

The application of Hirshfeld atom refinement (HAR) fragmentation is demonstrated for the refinement of metal-organic framework (MOF) crystal structures. The presented method enables anisotropic refinement of imidazolate hydrogen atoms, as well as complex analysis of solvent disorder within MOF pores. The data used were derived from standard resolution in-house single crystal X-ray diffraction measurements, demonstrating that high quality structural analysis of MOFs no longer requires access to neutron or synchrotron facilities.

The effects of experimentally obtained electron correlation and polarization on electron densities and exchange-correlation potentials.

In X-ray constrained wavefunction (XCW) fitting, external information, such as electron correlation and polarization, is included into a single-determinantal isolated-molecule wavefunction. In a first step, we show that the extraction of these two physical effects by XCW fitting is complete and accurate by comparing to theoretical reference calculations. In a second step, we show that fitting to data from single-crystal x-ray diffraction measurements provides the same results qualitatively and how the physical effects can be separated, although always inherently convolved in the experiment. We further demonstrate that exchange-correlation potentials are systematically affected by XCW fitting in a physically meaningful way, which could be exploited for method development in quantum chemistry, subject to some remaining challenges that we also outline.

Hirshfeld Atom Refinement of Metal-Organic Complexes: Treatment of Hydrogen Atoms Bonded to Transition Metals.

Hydrogen positions in hydrides play a key role in hydrogen storage materials and high-temperature superconductors. Our recently published study of five crystal structures of transition-metal-bound hydride complexes showed that using aspherical atomic scattering factors for Hirshfeld atom refinement (HAR) resulted in a systematic elongation of metal-hydrogen bonds compared to using spherical scattering factors with the Independent Atom Model (IAM). Even though only standard-resolution X-ray data was used, for the highest-quality data, we obtained excellent agreement between the X-ray and the neutron-derived bond lengths. We present an extended version of this study including 10 crystal structures of metal-organic complexes containing hydrogen atoms bonded to transition-metal atoms for which both X-ray and neutron data are available. The neutron structures were used as a benchmark, and the X-ray structures were refined by applying Hirshfeld atom refinement using various basis sets and DFT functionals in order to investigate the influence of the technical aspects on the length of metal-hydrogen bonds. The result of including relativistic effects in the Hamiltonian and using a cluster of multipoles simulating interactions with a crystal environment during wave function calculations was examined. The effect of the data quality on the final result was also evaluated. The study confirms that a high quality of experimental data is the key factor allowing us to obtain significant improvement in transition metal (TM)-hydrogen bond lengths from HAR in comparison with the IAM. Individual adjustments and better choices of the basis set can improve hydrogen positions. Average differences between TM-H bond lengths obtained with various DFT functionals upon including relativistic effects or between double-ζ and triple-ζ basis sets were not statistically significant. However, if all bonds formed by H atoms were considered, significant differences caused by different refinement strategies were observed. Finally, we examined the refinement of atomic thermal motions. Anisotropic refinement of hydrogen thermal motions with HAR was feasible only in some cases, and isotropically refined hydrogen thermal motions were in similar agreement with neutron values whether obtained with HAR or with the IAM.

Fragmentation and transferability in Hirshfeld atom refinement.

Hirshfeld atom refinement (HAR) is one of the most effective methods for obtaining accurate structural parameters for hydrogen atoms from X-ray diffraction data. Unfortunately, it is also relatively computationally expensive, especially for larger molecules due to wavefunction calculations. Here, a fragmentation approach has been tested as a remedy for this problem. It gives an order of magnitude improvement in computation time for larger organic systems and is a few times faster for metal-organic systems at the cost of only minor differences in the calculated structural parameters when compared with the original HAR calculations. Fragmentation was also applied to polymeric and disordered systems where it provides a natural solution to problems that arise when HAR is applied. The concept of fragmentation is closely related to the transferable aspherical atom model (TAAM) and allows insight into possible ways to improve TAAM. Hybrid approaches combining fragmentation with the transfer of atomic densities between chemically similar atoms have been tested. An efficient handling of intermolecular interactions was also introduced for calculations involving fragmentation. When applied in fragHAR (a fragmentation approach for polypeptides) as a replacement for the original approach, it allowed for more efficient calculations. All of the calculations were performed with a locally modified version of Olex2 combined with a development version of discamb2tsc and ORCA. Care was taken to efficiently use the power of multicore processors by simple implementation of load-balancing, which was found to be very important for lowering computational time.

virusMED: an atlas of hotspots of viral proteins.

Metal binding sites, antigen epitopes and drug binding sites are the hotspots in viral proteins that control how viruses interact with their hosts. virusMED (virus Metal binding sites, Epitopes and Drug binding sites) is a rich internet application based on a database of atomic interactions around hotspots in 7041 experimentally determined viral protein structures. 25306 hotspots from 805 virus strains from 75 virus families were characterized, including influenza, HIV-1 and SARS-CoV-2 viruses. Just as Google Maps organizes and annotates points of interest, virusMED presents the positions of individual hotspots on each viral protein and creates an atlas upon which newly characterized functional sites can be placed as they are being discovered. virusMED contains an extensive set of annotation tags about the virus species and strains, viral hosts, viral proteins, metal ions, specific antibodies and FDA-approved drugs, which permits rapid screening of hotspots on viral proteins tailored to a particular research problem. The virusMED portal (https://virusmed.biocloud.top) can serve as a window to a valuable resource for many areas of virus research and play a critical role in the rational design of new preventative and therapeutic agents targeting viral infections.

Relativistic Hirshfeld atom refinement of an organo-gold(I) compound.

The main goal of this study is the validation of relativistic Hirshfeld atom refinement (HAR) as implemented in Tonto for high-resolution X-ray diffraction datasets of an organo-gold(I) compound. The influence of the relativistic effects on statistical parameters, geometries and electron density properties was analyzed and compared with the influence of electron correlation and anharmonic atomic motions. Recent work in this field has indicated the importance of relativistic effects in the static electron density distribution of organo-mercury compounds. This study confirms that differences in electron density due to relativistic effects are also of significant magnitude for organo-gold compounds. Relativistic effects dominate not only the core region of the gold atom, but also influence the electron density in the valence and bonding region, which has measurable consequences for the HAR refinement model parameters. To study the effects of anharmonic motion on the electron density distribution, dynamic electron density difference maps were constructed. Unlike relativistic and electron correlation effects, the effects of anharmonic nuclear motion are mostly observed in the core area of the gold atom.

Towards accurate and precise positions of hydrogen atoms bonded to heavy metal atoms.

A comparison of five X-ray structures of transition-metal-bound hydride complexes, successfully refined using Hirshfeld Atom Refinement (HAR) against low resolution X-ray diffraction data (including the positions and ADPs of all hydrogen atoms), with neutron structures shows that using aspherical atomic scattering factors instead of spherical ones results in systematic elongation of metal-hydrogen bonds, which in the case of the highest-quality data leads to excellent agreement of the X-ray and the neutron-derived bond lengths.

Correction: Towards accurate and precise positions of hydrogen atoms bonded to heavy metal atoms.

Correction for 'Towards accurate and precise positions of hydrogen atoms bonded to heavy metal atoms' by Magdalena Woinska et al., Chem. Commun., 2021, 57, 3652-3655, DOI: 10.1039/D0CC07661A.

State-of-the-Art Data Management: Improving the Reproducibility, Consistency, and Traceability of Structural Biology and in Vitro Biochemical Experiments.

Efficient and comprehensive data management is an indispensable component of modern scientific research and requires effective tools for all but the most trivial experiments. The LabDB system developed and used in our laboratory was originally designed to track the progress of a structure determination pipeline in several large National Institutes of Health (NIH) projects. While initially designed for structural biology experiments, its modular nature makes it easily applied in laboratories of various sizes in many experimental fields. Over many years, LabDB has transformed into a sophisticated system integrating a range of biochemical, biophysical, and crystallographic experimental data, which harvests data both directly from laboratory instruments and through human input via a web interface. The core module of the system handles many types of universal laboratory management data, such as laboratory personnel, chemical inventories, storage locations, and custom stock solutions. LabDB also tracks various biochemical experiments, including spectrophotometric and fluorescent assays, thermal shift assays, isothermal titration calorimetry experiments, and more. LabDB has been used to manage data for experiments that resulted in over 1200 deposits to the Protein Data Bank (PDB); the system is currently used by the Center for Structural Genomics of Infectious Diseases (CSGID) and several large laboratories. This chapter also provides examples of data mining analyses and warnings about incomplete and inconsistent experimental data. These features, together with its capabilities for detailed tracking, analysis, and auditing of experimental data, make the described system uniquely suited to inspect potential sources of irreproducibility in life sciences research.

Hirshfeld atom like refinement with alternative electron density partitions.

Hirshfeld atom refinement is one of the most successful methods for the accurate determination of structural parameters for hydrogen atoms from X-ray diffraction data. This work introduces a generalization of the method [generalized atom refinement (GAR)], consisting of the application of various methods of partitioning electron density into atomic contributions. These were tested on three organic structures using the following partitions: Hirshfeld, iterative Hirshfeld, iterative stockholder, minimal basis iterative stockholder and Becke. The effects of partition choice were also compared with those caused by other factors such as quantum chemical methodology, basis set, representation of the crystal field and a combination of these factors. The differences between the partitions were small in terms of R factor (e.g. much smaller than for refinements with different quantum chemistry methods, i.e. Hartree-Fock and coupled cluster) and therefore no single partition was clearly the best in terms of experimental data reconstruction. In the case of structural parameters the differences between the partitions are comparable to those related to the choice of other factors. We have observed the systematic effects of the partition choice on bond lengths and ADP values of polar hydrogen atoms. The bond lengths were also systematically influenced by the choice of electron density calculation methodology. This suggests that GAR-derived structural parameters could be systematically improved by selecting an optimal combination of the partition and quantum chemistry method. The results of the refinements were compared with those of neutron diffraction experiments. This allowed a selection of the most promising partition methods for further optimization of GAR settings, namely the Hirshfeld, iterative stockholder and minimal basis iterative stockholder.

On the accuracy and precision of X-ray and neutron diffraction results as a function of resolution and the electron density model.

X-ray diffraction is the main source of three-dimensional structural information. In total, more than 1.5 million crystal structures have been refined and deposited in structural databanks (PDB, CSD and ICSD) to date. Almost 99.7% of them were obtained by approximating atoms as spheres within the independent atom model (IAM) introduced over a century ago. In this study, X-ray datasets for single crystals of hydrated α-oxalic acid were refined using several alternative electron density models that abandon the crude spherical approximation: the multipole model (MM), the transferable aspherical atom model (TAAM) and the Hirshfeld atom refinement (HAR) model as a function of the resolution of X-ray data. The aspherical models (MM, TAAM, HAR) give far more accurate and precise single-crystal X-ray results than IAM, sometimes identical to results obtained from neutron diffraction and at low resolution. Hence, aspherical approaches open new routes for improving existing structural information collected over the last century.

Comparison of metal-bound and unbound structures of aminopeptidase B proteins from Escherichia coli and Yersinia pestis.

Protein degradation by aminopeptidases is involved in bacterial responses to stress. Escherichia coli produces two metal-dependent M17 family leucine aminopeptidases (LAPs), aminopeptidase A (PepA) and aminopeptidase B (PepB). Several structures have been solved for PepA as well as other bacterial M17 peptidases. Herein, we report the first structures of a PepB M17 peptidase. The E. coli PepB protein structure was determined at a resolution of 2.05 and 2.6 Å. One structure has both Zn2+ and Mn2+ , while the second structure has two Zn2+ ions bound to the active site. A 2.75 Å apo structure is also reported for PepB from Yersinia pestis. Both proteins form homohexamers, similar to the overall arrangement of PepA and other M17 peptidases. However, the divergent N-terminal domain in PepB is much larger resulting in a tertiary structure that is more expanded. Modeling of a dipeptide substrate into the C-terminal LAP domain reveals contacts that account for PepB to uniquely cleave after aspartate.

Energetics of interactions in the solid state of 2-hydroxy-8-X-quinoline derivatives (X = Cl, Br, I, S-Ph): comparison of Hirshfeld atom, X-ray wavefunction and multipole refinements.

In this work, two methods of high-resolution X-ray data refinement: multipole refinement (MM) and Hirshfeld atom refinement (HAR) - together with X-ray wavefunction refinement (XWR) - are applied to investigate the refinement of positions and anisotropic thermal motion of hydrogen atoms, experiment-based reconstruction of electron density, refinement of anharmonic thermal vibrations, as well as the effects of excluding the weakest reflections in the refinement. The study is based on X-ray data sets of varying quality collected for the crystals of four quinoline derivatives with Cl, Br, I atoms and the -S-Ph group as substituents. Energetic investigations are performed, comprising the calculation of the energy of intermolecular interactions, cohesive and geometrical relaxation energy. The results obtained for experimentally derived structures are verified against the values calculated for structures optimized using dispersion-corrected periodic density functional theory. For the high-quality data sets (the Cl and -S-Ph compounds), both MM and XWR could be successfully used to refine the atomic displacement parameters and the positions of hydrogen atoms; however, the bond lengths obtained with XWR were more precise and closer to the theoretical values. In the application to the more challenging data sets (the Br and I compounds), only XWR enabled free refinement of hydrogen atom geometrical parameters, nevertheless, the results clearly showed poor data quality. For both refinement methods, the energy values (intermolecular interactions, cohesive and relaxation) calculated for the experimental structures were in similar agreement with the values associated with the optimized structures - the most significant divergences were observed when experimental geometries were biased by poor data quality. XWR was found to be more robust in avoiding incorrect distortions of the reconstructed electron density as a result of data quality issues. Based on the problem of anharmonic thermal motion refinement, this study reveals that for the most correct interpretation of the obtained results, it is necessary to use the complete data set, including the weak reflections in order to draw conclusions.

Validation of X-ray Wavefunction Refinement.

In this work, the quality of the electron density in crystals reconstructed by the multipolar model (MM) and by X-ray wavefunction refinement (XWR) is tested on a set of high-resolution X-ray diffraction data sets of four amino acids and six tripeptides. It results in the first thorough validation of XWR. Agreement statistics, figures of merit, residual- and deformation-density maps, as well as atomic displacement parameters are used to measure the quality of the reconstruction relative to the measured structure factors. Topological analysis of the reconstructed density is carried out to obtain atomic and bond-topological properties, which are subsequently compared to the values derived from benchmarking periodic DFT geometry optimizations. XWR is simultaneously in better agreement than the MM with both benchmarking theory and the measured diffraction pattern. In particular, the obvious problems with the description of polar bonds in the MM are significantly reduced by using XWR. Similarly, modeling of electron density in the vicinity of hydrogen atoms with XWR is visibly improved.

Hydrogen atoms can be located accurately and precisely by x-ray crystallography.

Precise and accurate structural information on hydrogen atoms is crucial to the study of energies of interactions important for crystal engineering, materials science, medicine, and pharmacy, and to the estimation of physical and chemical properties in solids. However, hydrogen atoms only scatter x-radiation weakly, so x-rays have not been used routinely to locate them accurately. Textbooks and teaching classes still emphasize that hydrogen atoms cannot be located with x-rays close to heavy elements; instead, neutron diffraction is needed. We show that, contrary to widespread expectation, hydrogen atoms can be located very accurately using x-ray diffraction, yielding bond lengths involving hydrogen atoms (A-H) that are in agreement with results from neutron diffraction mostly within a single standard deviation. The precision of the determination is also comparable between x-ray and neutron diffraction results. This has been achieved at resolutions as low as 0.8 Å using Hirshfeld atom refinement (HAR). We have applied HAR to 81 crystal structures of organic molecules and compared the A-H bond lengths with those from neutron measurements for A-H bonds sorted into bonds of the same class. We further show in a selection of inorganic compounds that hydrogen atoms can be located in bridging positions and close to heavy transition metals accurately and precisely. We anticipate that, in the future, conventional x-radiation sources at in-house diffractometers can be used routinely for locating hydrogen atoms in small molecules accurately instead of large-scale facilities such as spallation sources or nuclear reactors.

Hirshfeld atom refinement for modelling strong hydrogen bonds.

High-resolution low-temperature synchrotron X-ray diffraction data of the salt L-phenylalaninium hydrogen maleate are used to test the new automated iterative Hirshfeld atom refinement (HAR) procedure for the modelling of strong hydrogen bonds. The HAR models used present the first examples of Z' > 1 treatments in the framework of wavefunction-based refinement methods. L-Phenylalaninium hydrogen maleate exhibits several hydrogen bonds in its crystal structure, of which the shortest and the most challenging to model is the O-H...O intramolecular hydrogen bond present in the hydrogen maleate anion (O...O distance is about 2.41 Å). In particular, the reconstruction of the electron density in the hydrogen maleate moiety and the determination of hydrogen-atom properties [positions, bond distances and anisotropic displacement parameters (ADPs)] are the focus of the study. For comparison to the HAR results, different spherical (independent atom model, IAM) and aspherical (free multipole model, MM; transferable aspherical atom model, TAAM) X-ray refinement techniques as well as results from a low-temperature neutron-diffraction experiment are employed. Hydrogen-atom ADPs are furthermore compared to those derived from a TLS/rigid-body (SHADE) treatment of the X-ray structures. The reference neutron-diffraction experiment reveals a truly symmetric hydrogen bond in the hydrogen maleate anion. Only with HAR is it possible to freely refine hydrogen-atom positions and ADPs from the X-ray data, which leads to the best electron-density model and the closest agreement with the structural parameters derived from the neutron-diffraction experiment, e.g. the symmetric hydrogen position can be reproduced. The multipole-based refinement techniques (MM and TAAM) yield slightly asymmetric positions, whereas the IAM yields a significantly asymmetric position.

N,N'-(Pyridine-2,6-di-yl)dibenzamide.

The mol-ecule of the title compound, C19H15N3O2, is completed by the application of crystallographic twofold symmetry, with the pyridine N atom lying on the rotation axis. The mol-ecular structure is approximately planar, the dihedral angle between the mean planes of the pyridine and benzene rings being 7.53 (11)°. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into a two-dimensional array perpendicular to the c axis.

Transferability of atomic multipoles in amino acids and peptides for various density partitions.

Multipole expansion of electron density distribution is an efficient tool for evaluating the energy of interactions in molecules. In as much as atoms in macromolecules such as peptides are modeled with certain types of atoms derived from small organic molecules, investigating transferability of atomic multipoles for various partitions of molecular electron density is an important issue. In this study, multipole moments up to hexadecapoles for types of atoms present in selected amino acids, as well as di- and tripeptides composed of these amino acids, are computed using three density partitions: Hansen-Coppens aspherical pseudoatoms formalism, Hirshfeld's stockholder partition, and Bader's atoms in molecules theory. Electron density of relevant molecules is derived in a procedure including molecular wave function ab initio calculation for isolated molecules in geometry from X-ray measurements, calculation of theoretical structure factors for molecules put in a pseudocubic cell, and multipole refinement as in crystallographic data processing and computation of multipoles. The results were compared to calculations of multipole moments in AIM and in stockholder density partitions obtained directly from molecular wave functions. The presented comparison does not point unambiguously to any particular influence of multipole refinement on moments obtained from these two partitions. The advantage of stockholder partitioning in terms of transferability of atomic multipoles is affirmed. AIM and pseudoatoms provide slightly less transferable multipoles of lower order. Higher rank of multipole expansion reveals a transferability improvement in the case of AIM and meaningful deterioration for pseudoatoms.