Correcting long-range electrostatic interactions in multiple hydrogen-bonded systems by experimental electron density.

Sarcoplasmic reticulum Ca(2+)-ATPase couples the motions and rearrangements of three cytoplasmic domains (A, P, and N) with Ca(2+) transport. We explored the role of electrostatic force in the domain dynamics in a rate-limiting phosphoenzyme (EP) transition by a systematic approach combining electrostatic screening with salts, computer analysis of electric fields in crystal structures, and mutations. Low KCl concentration activated and increasing salt above 0.1 m inhibited the EP transition. A plot of the logarithm of the transition rate versus the square of the mean activity coefficient of the protein gave a linear relationship allowing division of the activation energy into an electrostatic component and a non-electrostatic component in which the screenable electrostatic forces are shielded by salt. Results show that the structural change in the transition is sterically restricted, but that strong electrostatic forces, when K(+) is specifically bound at the P domain, come into play to accelerate the reaction. Electric field analysis revealed long-range electrostatic interactions between the N and P domains around their hinge. Mutations of the residues directly involved and other charged residues at the hinge disrupted in parallel the electric field and the structural transition. Favorable electrostatics evidently provides a low energy path for the critical N domain motion toward the P domain, overcoming steric restriction. The systematic approach employed here is, in general, a powerful tool for understanding the structural mechanisms of enzymes.

Exploring nonlinear optical (NLO) functional motifs (FM, the structural origin of NLO efficiency) is vital for the rational design of NLO materials. Normal spectrum techniques applied in studying photon exciting materials are invalid for NLO materials, in which electrons are not excited substantially but only distorted under laser. A general strategy of determining NLO FM is proposed by comparative studies of experimental electron density (ED) without and under the laser. The in situ experimental ED and wavefunction of typical NLO material LiB3O5 (LBO) under dark and 360 and 1064 nm lasers are investigated. Compared with the initial state under dark, the ED of [B3O5]− unit at functional states under laser irradiation exhibits remarkable changes of topological atomic and bond properties, confirming the NLO FM being [B3O5]−. The work extracts for the first time the FM of a NLO material experimentally and highlights the crucial role of in situ ED analysis in studying NLO mechanisms.

On the application of complete orthonormal atomic basis sets to x-rays diffracted by a thermally excited molecule

Topological analysis of experimental and theoretical (molecular and crystal) electron densities of p-nitroaniline and p-amino-p'-nitrobiphenyl reveals considerable discrepancies between experiment and theory for the bond critical points properties. Particularly large differences occur for the positive curvature along the bond path (lambda 3). The differences become somewhat smaller when more extended basis sets and correlation effects are introduced in the theoretical calculations. The effect of the crystal matrix on the properties of bond critical points is evaluated for the p-nitroaniline molecule using the 6-21G** and 6-31G** basis sets. The differences between the isolated molecule and the molecule in the crystal are too small to explain the quantitative disagreement between the theoretical and experimental topologies reported in the literature and found in the current study. For most bonds, the observed changes in the properties of the electron density agree well for both basis sets but some discrepancies are found for changes in lambda 3 for N-H and aromatic C-C bonds. When the theoretical densities are projected into the multipole density functions through refinement of the theoretical structure factors, the topological properties change and differences between theory and experiment are reduced. The main origin of the observed discrepancies is attributed to the nature of the radial functions in the experimental multipole model.

The investigation of the intermolecular interactions between platinum-based anticancer drugs and lipid bilayers is of special relevance to unveil the mechanisms involved in different steps of the anticancer mode of action of these drugs. We have simulated the permeation of cisplatin through a model membrane composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids by means of umbrella sampling classical molecular dynamics simulations. The initial physisorption of cisplatin into the polar region of the lipid membrane is controlled by long-range electrostatic interactions with the choline groups in a first step and, in a second step, by long-range electrostatic and hydrogen bond interactions with the phosphate groups. The second half of the permeation pathway, in which cisplatin diffuses through the nonpolar region of the bilayer, is characterized by the drop of the interactions with the polar heads and the rise of attractive interactions with the non-polar tails, which are dominated by van der Waals contributions. The permeation free-energy profile is explained by a complex balance between the drug/lipid interactions and the energy and entropy contributions associated with the dehydration of the drug along the permeation pathway and with the decrease and increase of the membrane ordering along the first and second half of the mechanism, respectively.

The kinetic, potential, and electronic energy distributions were calculated from the experimental electron density using the DFT functionals for the energetic β-form of 5-nitro-2,4-dihydro-3H-1,2,4-triazol-3-one (NTO), biguanidinium dinitramide, (BIGH)(DN), and biguanidinium bis-dinitramide, (BIGH2)(DN)2. The spatial distribution of the electronic energy density is shown to be a useful descriptor of the chemical bonding and intermolecular interactions, in addition to the electron density and Laplacian distributions. Also, the kinetic energies and atomic charges have been integrated over the atomic basins. The examination of these spatial and integrated values allowed us to more completely describe the nature of atomic and molecular interactions.

An experimental charge density study of a 1 : 1 complex of Cu-cfx (cfx = ciprofloxacin), 1 [Cu(cfx)(H(2)O)(3)]SO4.2H(2)O, has been performed using single-crystal X-ray diffraction data collected at 100 K using conventional Mo Kalpha radiation. Metal-ligand (ML) bonds and hydrogen bonds (HBs) have been analysed using topological analysis of the electron density with the atoms in molecules (AIM) approach. The copper atom binds to two oxygen atoms in one end of the zwitterionic form of the cfx molecule, in addition to forming bonds with three water molecules, forming a square pyramidal coordination geometry. AIM decomposition of the experimental electron density establishes that the copper atom binds more strongly to the cfx molecule than to the water molecules, suggesting that the latter can be detached leaving behind a reactive, water-free Cu-cfx complex available for interaction with e.g. a macromolecular site. AIM analysis of the extensive hydrogen bond pattern reveals that the positively charged N-end of the zwitterionic cfx forms a relatively strong N-H-O hydrogen bond implying that this region of cfx may play an important role in the docking process in the active site. Visualisation and statistics of selected density derived properties on the molecular surface of the isolated cfx molecule vs its metal complexed counterpart points out regions of potential reactivity. The effect of the fluorine atom is to expand the negative region of the electrostatic potential, while the nitrogen end is heavily electropositive and willingly donates to--for molecular docking purposes--relatively strong hydrogen bonding. The Cu atom is highlighted as a potentially highly reactive site which is likely to interact strongly with any given negative ligand.

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.

The electron densities in three crystal forms of piracetam (triclinic form II, monoclinic form III, and triclinic piracetam monohydrate) were derived from high resolution X-ray diffraction experiments carried out at 100 K. For comparison, quantum mechanics calculations were also performed for the three compounds. The experimental electron density was refined using the Hansen–Coppens multipole model. The electron deformation density and the electrostatic potential were carefully analyzed in the three forms of piracetam. The atomic charges obtained by the flux of the electric field were found in excellent agreement with those obtained by the conventional volume integration method. The charge values compare qualitatively well with those obtained by theoretical calculations. The total electrostatic force exerted on each atom of the molecule has been investigated by using the Maxwell stress tensor as well as the interatomic forces. The experimental electrostatic interaction energies between dimers in the three...

Exploring the bond topological and electrostatic properties of benzimidazole molecule via experimental and theoretical charge density study

Stereoelectronic interaction lp(O1) → σ*(N1-O2) in a O-N-O unit was analyzed by means of R. Bader's Atoms in Molecule theory on the basis of X-ray diffraction data for dimethyl-(2R,4aR,5S,7R)-2,5,7-triphenylhexahydro-4H-[1,2]oxazino[2,3-b][1,2]oxazine-4,4-dicarboxylate. Atomic energies obtained by applying this approach to both the experimental and theoretical electron densities were used to probe the energy of this strong stereoelectronic interaction, giving consistent results with the NBO analysis, although showing its destabilizing character.

The AlB 2 structure-type consists of layers of B 6 -rings and a metal atom located in the hexagonal prismatic voids.With the increase of the ratio of M:B, the B 6 -rings form chains (M 3 B 4 ) and chains of single B-atoms besides B 6 -chains (M 5 B 6 ).Besides the metal atoms in the hexagonal prismatic voids, there are interstitial metal atoms.Kiessling [1] first investigated the crystal structure of Ta 3 B 4 and found very different distances in the B 6 -ring-chains.One bond was very short (1.57Å), the other remarkably long (1.85 Å).Hoffmann et al. [2] investigated this structure by Extended Hückel calculations.They tried to find out why the distances in Ta 3 B 4 are so different from the ones found in MB 2 and M 5 B 6 .In order to get information on the bonding situation in these three types of transition metal borides, we performed DFT-LAPW-calculations and we also optimized the geometry.This optimization resulted in very similar structures for all M 3 B 4 with similar distances between all atoms of the B 6 -ring.So the structure found by Kiessling could not be verified.Maybe his results were biased because of the high absorption coefficient of Ta 3 B 4 .The optimized and the not optimized structures were examined by QTAIM-Analysis as introduced by Bader [3].The bondig between the M-atoms and the B-atoms are clearly ionic.The M in the hexagonal prismatic voids is more positive charged than the other ones in the structure.Also with increasing atomic number, the metal atoms in the structures become more positive charged.There is a small difference in the negative charge of the two different B-atoms of the B 6 -ring-chain.The densitiy at the bond critical points in the B 6 -ring-chain in M 5 B 6 is a bit smaller than in the other structures.

Experimental electron densities and derived properties have been determined for the two energetic materials CL-20 (3,5,9,11-tetraacetyl-14-oxo-1,3,5,7,9,11-hexaazapentacyclo-[5.5.3.02,6.04,10.08,12]pentadecane), and FOX-7 (1,1-diamino-2,2-dinitroethylene) from single-crystal diffraction. Synchrotron data extending to high scattering angles were measured at low temperature. Low figures-of-merit and excellent residuals were obtained. The Hansen & Coppens multipole-model electron density was compared with results from theoretical calculations via structure factors simulating an experiment. Chemical bonding in the molecules is discussed and a topological analysis gives insight especially into the character of those bonds that are thought to play a key role in the decomposition of the molecules. A comparison of theoretical and experimental electrostatic potentials shows no obvious evidence supporting earlier findings on other nitroheterocyclic molecules that electron-density maxima near the C-NO(2) bonds mapped on the electron-density isosurface can be correlated with impact sensitivities. For FOX-7 periodic Hartree-Fock calculations were performed to investigate the influence of the crystal field on the electron density distribution.

Reported here is an entirely new application of experimental electron density (EED) in the study of magnetic anisotropy of single-molecule magnets (SMMs). Among those SMMs based on one single transition metal, tetrahedral CoII-complexes are prominent, and their large zero-field splitting arises exclusively from coupling between the d and dxy orbitals. Using very low temperature single-crystal synchrotron X-ray diffraction data, an accurate electron density (ED) was obtained for a prototypical SMM, and the experimental d-orbital populations were used to quantify the dxy-d coupling, which simultaneously provides the composition of the ground-state Kramers doublet wave function. Based on this experimentally determined wave function, an energy barrier for magnetic relaxation in the range 193-268 cm-1 was calculated, and is in full accordance with the previously published value of 230 cm-1 obtained from near-infrared spectroscopy. These results provide the first clear and direct link between ED and molecular magnetic properties.

For the fungal metabolite citrinin, C13H14O5, the total experimental electron distribution ρ(r) and its Laplacian [Formula: see text] have been obtained from an extensive set (36 564 measurements) of single-crystal X-ray diffracted intensities at a temperature of 19 ± 2 K. Relevant steps in data collection and processing are reported. The resulting 7698 independent intensity data have been analysed with a multipole (pseudoatoms) formalism. The topological properties of ρ(r) have been determined according to the quantum theory of atoms in molecules. CC and CO bond path lengths have been obtained by numerical integration; their values are found to be well correlated with those of the electron density at the bond critical points. Topological features have been used to characterize the extension of the conjugated system of the molecule, and to confirm the stability of its rings, particularly the two formed by intramolecular H bonds. Maps of [Formula: see text] are presented, showing details in the valence charge distribution and providing a very sensitive tool for analysing dependence of the density on the model adopted to interpret X-ray data. The known chemical reactivity of the molecule towards nucleophiles at a Csp2 atom is confirmed by the shape of the molecular reactive surface (the zero envelope of [Formula: see text]). Key words: experimental electron density, low-temperature X-ray diffraction, topological analysis, Laplacian of ρ.