Anharmonic Thermal Motion Modelling in the Experimental XRD Charge Density Determination of 1-Methyluracil at T = 23 K.

The experimental electron density distribution (EDD) of 1-methyluracil (1-MUR) was obtained by single crystal X-ray diffraction (XRD) experiments at 23 K. Four different structural models fitting an extensive set of XRD data to a resolution of (sinθ/λ)max = 1.143 Å-1 are compared. Two of the models include anharmonic temperature factors, whose inclusion is supported by the Hamilton test at a 99.95% level of confidence. Positive Fourier residuals up to 0.5 eÅ-3 in magnitude were found close to the methyl group and in the region of hydrogen bonds. Residual density analysis (RDA) and molecular dynamics simulations in the solid-state demonstrate that these residuals can be likely attributed to unresolved disorder, possibly dynamical and long-range in nature. Atomic volumes and charges, molecular moments up to hexadecapoles, as well as maps of the molecular electrostatic potential were obtained from distributed multipole analysis of the EDD. The derived electrostatic properties neither depend on the details of the multipole model, nor are significantly affected by the explicit inclusion of anharmonicity in the least-squares model. The distribution of atomic charges in 1-MUR is not affected by the crystal environment in a significant way. The quality of experimental findings is discussed in light of in-crystal and gas-phase quantum simulations.

Physicochemical properties of zwitterionic L- and DL-alanine crystals from their experimental and theoretical charge densities.

The total experimental electron density distributions rho(r) of zwitterionic L- and DL-alanine crystals, as derived from extensive sets of X-ray diffracted intensities collected at 23 and 19 K, are compared to gain an insight into the different physical properties of the two related chiral compounds in the solid state and to explore the extent of the rho(r) transferability. Relevant parameters that characterize the two crystal forms are obtained, showing differences and similarities in terms of (i) geometric descriptors, (ii) topological indexes, (iii) molecular electrostatic potential Phi(r) distributions, (iv) atomic volumes and charges, (v) molecular electric moments, and (vi) electrostatic interaction energies. To assess the relative stability of the racemate with respect to the pure enantiomer, the crystal lattice energies, as obtained through DFT fully periodic calculations, are also discussed and compared with the experimental sublimation enthalpies after correction for the proton-transfer energies. In-crystal group charges, evaluated with the quantum theory of atoms in molecules, are found to be transferable between the racemic and the pure enantiomer, at variance with group volumes. Similarly, molecular first and third moments are not strictly transferable and indicate that for the zwitterionic alanine molecule the molecular charge distribution in the DL-crystal is more polarized in the c direction by about 10%. By contrast, quantitative agreement is observed for second and fourth moments. Significant differences arise from (1) the crystal packing of the dipole vectors, which are aligned in an antiparallel fashion in the L-crystal, to be compared with a parallel alignment in the racemate, due the polar space group Pna21 of the latter, (2) the strongly attractive electrostatic energy of a homochiral pair in the L-crystal, which is opposed to the corresponding heterochiral pair in the DL-crystal form. The difference between these Ees values amounts to 135-150 kJ mol(-1). Despite this, the two crystal forms are predicted as equally thermodynamically favored by the theoretical P-B3LYP estimates of the crystal lattice energies. Finally, the necessity of an upgrading of the dispersion and exchange-repulsion terms currently adopted within the experimental charge density approach to intermolecular interactions is recognized and discussed.

Progress in the understanding of drug-receptor interactions, part 2: experimental and theoretical electrostatic moments and interaction energies of an angiotensin II receptor antagonist (C30H30N6(O)3S).

A combined experimental and theoretical charge density study of an angiotensin II receptor antagonist (1) is presented focusing on electrostatic properties such as atomic charges, molecular electric moments up to the fourth rank and energies of the intermolecular interactions, to gain an insight into the physical nature of the drug-receptor interaction. Electrostatic properties were derived from both the experimental electron density (multipole refinement of X-ray data collected at T=17 K) and the ab initio wavefunction (single molecule and fully periodic calculations at the DFT level). The relevance of SO and SN intramolecular interactions on the activity of 1 is highlighted by using both the crystal and gas-phase geometries and their electrostatic nature is documented by means of QTAIM atomic charges. The derived electrostatic properties are consistent with a nearly spherical electron density distribution, characterised by an intermingling of electropositive and -negative zones rather than by a unique electrophilic region opposed to a nucleophilic area. This makes the first molecular moment scarcely significant and ill-determined, whereas the second moment is large, significant and highly reliable. A comparison between experimental and theoretical components of the third electric moment shows a few discrepancies, whereas the agreement for the fourth electric moment is excellent. The most favourable intermolecular bond is show to be an NHN hydrogen bond with an energy of about 50 kJ mol(-1). Key pharmacophoric features responsible for attractive electrostatic interactions include CHX hydrogen bonds. It is shown that methyl and methylene groups, known to be essential for the biological activity of the drug, provide a significant energetic contribution to the total binding energy. Dispersive interactions are important at the thiophene and at both the phenyl fragments. The experimental estimates of the electrostatic contribution to the intermolecular interaction energies of six molecular pairs, obtained by a new model proposed by Spackman, predict the correct relative electrostatic energies with no exceptions.

Progress in the understanding of drug-receptor interactions, Part 1: experimental charge-density study of an angiotensin II receptor antagonist (C30H30N6O3S) at T = 17 K.

An experimental study of the electron-density distribution rho(r) in an angiotensin II receptor antagonist 1 has been made on the basis of single-crystal X-ray diffraction data collected at a low temperature. The crystal structure of 1 consists of infinite ribbons in which molecules are connected by an N-H...N hydrogen bond and several interactions of the C-H...O, C-H...N, and C-H...S type. The molecular conformation, characterized by the syn orientation of a tetrazole and a pyrimidinone ring with respect to a phenyl spacer group, is stabilized by two short SO and SN intramolecular contacts between a substituted thiophene fragment and the other two heterocycles of 1. The electrostatic nature of these interactions is documented. Furthermore, the Laplacian of rho(r) in the plane defined by the sulfur, oxygen, and nitrogen atoms involved in these interactions shows their strongly directional character as the regions of charge concentration on the valence shell of the nitrogen and oxygen atoms directly face the regions of charge depletion on the valence shell of the sulfur atom. All the chemical bonds and the relevant intra- and intermolecular interactions of 1 have been quantitatively described by the topological analysis of rho(r). Simple relationships between the bond path lengths (R(b)) and the values of rho at the bond critical points (rho(bcp)) have been obtained for the 28 C-C bonds, the seven N-C bonds, and the four O-C bonds. For the first two classes of bonds the relationship is in the form of a straight line, whose parameters, for the C-C bonds, agree, within experimental uncertainty, with those previously derived in our laboratory from a 19 K X-ray diffraction study of crystals of a different compound. Maps of the molecular electrostatic potential phi(r) derived from the experimental charge density display features that are important for the drug-receptor recognition of 1.