On the role of data quality in experimental charge-density studies.

High-resolution X-ray diffraction data were collected at T = 19 K from two similar spherical crystals of the fungal metabolite citrinin, C13H14O5. The two data sets were of markedly different quality, one data set (MQ, medium quality) comprising a single octant of the reciprocal lattice and including reflections with obviously peculiar intensity profiles while the second (HQ, high quality) comprised a hemisphere of reflections and showed no flawed profiles. Parallel multipolar refinements were carried out for both. While most of the resulting geometric parameters, including bond lengths and angles, were in close agreement (the standard uncertainties were approximately twice as large for the MQ data, reflecting the smaller number of observations), the agreement is noticeably worse for electronic properties such as electron densities and their Laplacians at the bond and ring critical points. These latter features are especially sensitive to the quality of the low-angle (and strong) intensities, which was not high for the MQ data. By contrast, the magnitudes of the molecular dipole moment from the two experiments are the same within 1 standard uncertainty, with an angle of about 13° between the two vectors. It is concluded that only true high-quality data allow a fully significant and quantitative analysis of the details of the experimental electron density ρexp, while high-resolution medium-quality data, measured at very low temperature and adequately processed, can still be used for a qualitative analysis, or for the derivation of overall electronic properties

Decoding conformational polymorphism in organic substances

Different polymorphs have different intensive physical properties and it is still impossible to predict from scratch if a change in the crystallization conditions will result in different crystal structures or not. In this contribution, possible correlations are highlighted among charge density features, molecular conformation and interaction energetics in the two known polymorphic forms of (DTC)[1,2], an isothiazole β-sultamic derivative. A tentative rationale is provided for the relative stability of the two forms on the basis of their different self-recognition patterns. Both polymorphs crystallize in the same P21/n space group and show very different non-covalent networks of weak C-H–X (X = N,O,π) interactions due to the dissimilar conformation of the asymmetric units (ASU). Accurate multi-temperature (100 K ≤ T ≤ 298 K) single-crystal X-Ray diffraction experiments were carried out and the evolution of crystal packing and self-recognition energetics were monitored through periodic quantum-mechanical calculations at fixed geometries. Preliminary results show that dispersive/repulsive and electrostatic non-covalent interactions dominate the crystal packing in both polymorphs. At T=100 K the form A have a tighter packing, as it shows a greater propensity in being involved in H bonds than B (see the Hirshfeld surface fingerprint plots[3] of forms A -left- and B -right- here reported). This reflects in greater density, whereas the estimated DFT cohesive energies of the two forms are similar. DTC has enough molecular flexibility to access various favourable arrangements during the nucleation, as the interconversion between the A and B conformers in the gas phase takes place with a very small activation energy. The possible role of the solvent in favouring either of the two observed conformations is discussed

Protein HP1028 from the human pathogen Helicobacter pyloribelongs to the lipocalin family

Helicobacter pylori is a bacterial pathogen that causes severe diseases, including gastritis, ulcers and gastric cancer. Although this bacterium has been extensively studied, the physiological functions of a large number of the proteins encoded by its genome are unknown. HP1028 is a protein that is relevant to colonization and to the survival of the bacterium in the stomach, but its function is not clearly understood. Bioinformatics studies suggest that HP1028 is a monomeric protein that is secreted in the H. pylori periplasm. The crystal structure of HP1028 has been determined at 2.6 A \u2da resolution using the SAD method. The three-dimensional structure of the protein reveals that it belongs to the lipocalin family, a group of proteins that bind and transport (often hydrophobic) small molecules. The structure of HP1028, together with the possible localization of the mature protein in the bacterial periplasm and the position of the hp1028 gene in the bacterial genome, point to a role in H. pylori chemotaxis

Intermolecular Recognition of the Antimalarial Drug Chloroquine: A Quantum Theory of Atoms in Molecules–Density Functional Theory Investigation of the Hydrated Dihydrogen Phosphate Salt from the 103 K X‑ray Structure

The relevant noncovalent interaction patterns responsible for intermolecular recognition of the antiplasmodial chloroquine (CQ) in its bioactive diprotonated form, CQH₂²⁺, are investigated. Chloroquine dihydrogen phosphate hydrated salt (<i>P</i>2₁/<i>c</i>) was crystallized by gel diffusion. A high-resolution single-crystal X-ray diffraction experiment was performed at 103(2) K, and a density functional theory model for the in-crystal electron density was derived, allowing the estimation of the interaction energies in relevant molecular pairs. H₂PO₄^– ions form infinite chains parallel to the monoclinic axis, setting up strong NH···O charge-assisted hydrogen bonds (CAHBs) with CQH₂²⁺. Couples of facing protonated quinoline rings are packed in a π···π stacked arrangement, whose contribution to the interaction energy is very low in the crystal and completely overwhelmed by Coulomb repulsion between positive aromatic rings. This questions the ability of CQ in setting up similar stacking interactions with the positively charged Fe-protoporphyrin moiety of the heme substrate in solution. When the heme/CQ adduct incorporates a Fe–N coordinative bond, stronger π···π interactions are instead established due to the lacking of net electrostatic repulsions. Yet, CAHBs among the protonated tertiary amine of CQ and the propionate group of heme still provide the leading stabilizing effect. Implications on possible modifications/improvements of the CQ pharmacophore are discussed

Rationalizing the Lacking of Inversion Symmetry in a Noncentrosymmetric Polar Racemate: An Experimental and Theoretical Study

The total charge density of PYRAC, a polar (<i>Pca</i>2₁) organic racemate with <i>Z</i>′ = 2, was derived from high-resolution single-crystal X-ray diffraction data at <i>T</i> = 100(2) K and periodic DFT calculations. The PYRAC asymmetric unit consists of a hydrogen-bonded pair of conformationally different enantiomers, A and B_i, where the subscript “i” indicates a reversed absolute configuration. The lattice stability was compared with that of centrosymmetric possibly competing structures, with the aim of understanding why a noncentrosymmetric lattice framework is obtained from a racemic mixture. The likelihood of specific intermolecular recognition processes among different conformers of PYRAC in the very first stages of nucleation was investigated by DFT simulations in vacuo. Two competing, equivalent interconversion pseudorotatory paths between the most stable A and the least stable B conformers were found. It results that molecules spend most of their time (≈53%) in the A conformation, whereas the B one is far less populated (≈7%). Therefore, centrosymmetric AA_i adducts are formed very frequently in the reaction liquor, whereas the BB_i ones are rare. Nevertheless, AA_i pairs produce crystal forms with cohesive energies and densities significantly less favorable than those estimated for the noncentrosymmetric heterochiral AB_i ones. Therefore, preference for <i>Z</i>′ = 2 in conjunction with noncentrosymmetric point and space groups results from the thermodynamic control of the crystallization process. The capability of forming extended hydrogen bond chains throughout the lattice appears to be a prerequisite to bind together the fundamental AB_i repeating units

Rationalizing the Lacking of Inversion Symmetry in a Noncentrosymmetric Polar Racemate: An Experimental and Theoretical Study

The total charge density of PYRAC, a polar (<i>Pca</i>2₁) organic racemate with <i>Z</i>′ = 2, was derived from high-resolution single-crystal X-ray diffraction data at <i>T</i> = 100(2) K and periodic DFT calculations. The PYRAC asymmetric unit consists of a hydrogen-bonded pair of conformationally different enantiomers, A and B_i, where the subscript “i” indicates a reversed absolute configuration. The lattice stability was compared with that of centrosymmetric possibly competing structures, with the aim of understanding why a noncentrosymmetric lattice framework is obtained from a racemic mixture. The likelihood of specific intermolecular recognition processes among different conformers of PYRAC in the very first stages of nucleation was investigated by DFT simulations in vacuo. Two competing, equivalent interconversion pseudorotatory paths between the most stable A and the least stable B conformers were found. It results that molecules spend most of their time (≈53%) in the A conformation, whereas the B one is far less populated (≈7%). Therefore, centrosymmetric AA_i adducts are formed very frequently in the reaction liquor, whereas the BB_i ones are rare. Nevertheless, AA_i pairs produce crystal forms with cohesive energies and densities significantly less favorable than those estimated for the noncentrosymmetric heterochiral AB_i ones. Therefore, preference for <i>Z</i>′ = 2 in conjunction with noncentrosymmetric point and space groups results from the thermodynamic control of the crystallization process. The capability of forming extended hydrogen bond chains throughout the lattice appears to be a prerequisite to bind together the fundamental AB_i repeating units