Claude Lecomte

Hydrogen bond strengths revealed by topological analyses of experimentally observed electron densities

Abstract Interatomic interactions such as hydrogen bonds (HB) can be adequately described and classified by the topological properties of the electron density ρ(r) at the (3,−1) critical points rCP where the gradients of ρ(r) vanish. We have analysed the topological properties of ρ(r) at the intermolecular critical points of 83 experimentally observed HBs [X–H⋯O (X=C,N,O)], using accurate X-ray diffraction experiments. In spite of different models, methods and experimental conditions employed to obtain the topological properties of ρ(r), we show that, for closed-shell interactions, the kinetic energy density G(rCP) and the potential energy density V(rCP) at the critical point depend exponentially on the H⋯O distance. Moreover, theoretical calculations for several HB dissociation energies follow the same law as does V(rCP), with a simple change of scale.

The Nature of Halogen⋅⋅⋅Halogen Interactions: A Model Derived from Experimental Charge‐Density Analysis

Slightly attractive: The attractive and anisotropic nature of the ClCl interaction in C(6)Cl(6) is experimentally demonstrated from an expansion of the electron density rho(r) around the chlorine nuclei. The interaction is explained in a model in which there is a bonding attraction involving electron-deficient (see picture, blue) and electron-rich (red) regions of adjacent Cl atoms.

Topological analysis of the electron density in hydrogen bonds

Topological analysis of the experimental electron density rho(r) in hydrogen-bonding regions has been carried out for a large number of organic compounds using different multipole models and techniques. Relevant systematic relationships between topological properties at the critical points and the usual geometric parameters are pointed out. Results involving X-ray data only and joint X-ray and neutron data, as well as special hydrogen bonding cases (symmetric, bifurcated, peptide bonds, etc.) are included and analysed in the same framework. A new classification of hydrogen bonds using the positive curvature of the electron density at the critical point [lambda(3)(r(CP))] is proposed.

Advances in protein and small-molecule charge-density refinement methods using MoPro

With an increasing number of biological macromolecule structures solved at ultra-high resolution and with the advances of supramolecular chemistry, it becomes necessary to extend to large systems experimental charge-density study methods that are usually applied to small molecules. The latest developments in the refinement program MoPro (Molecular Properties), dedicated to the charge-density refinement at (sub)atomic resolution of structures ranging from small molecules to biological macromolecules, are presented. MoPro uses the Hansen & Coppens [Acta Cryst. (1978), A34, 909–921] multipolar pseudo-atom model for the electron-density refinement. Alternative methods are also proposed, such as modelling bonding and lone-pair electron density by virtual spherical atoms. For proteins at atomic resolution, a charge-density database developed in the laboratory enables the transfer of multipolar parameters. The program allows complex refinement strategies to be written and has numerous restraints, constraints and analysis tools for use in the structure and electron-density analysis. New kappa and multipolar parameter restraints/constraints are also implemented and discussed. Furthermore, constraints on the electron density, such as local symmetry and atom equivalence, are easily defined. Some examples of applications, from small molecules to large unit cells (including the enzyme aldose reductase), are given in order to guide the MoPro user and to show the large field of applicability of this code.

Conformations and coordination schemes of carboxylate and carbamoyl derivatives of the tetraazamacrocycles cyclen and cyclam, and the relation to their protonation states

Abstract This paper discusses and rationalizes the metal coordination pattern of 12- and 14-membered tetraazamacrocyclic carboxylate and carbamoyl ligands based on the cyclen and cyclam framework in light of their acido–basic properties. Structural and protonation data are reviewed in order to illustrate the influence of the free ligands protonation state and of the pH conditions during the complexation reaction on the final coordination mode of the metallic cations.

Refinement of proteins at subatomic resolution with MOPRO

Crystallography at subatomic resolution permits the observation and measurement of the non-spherical character of the atomic electron density. Charge density studies are being performed on molecules of increasing size. The MOPRO least-squares refinement software has thus been developed, by extensive modifications of the program MOLLY, for protein and supramolecular chemistry applications. The computation times are long because of the large number of reflections and the complexity of the multipolar model of the atomic electron density; the structure factor and derivative calculations have thus been parallelized. Stereochemical and dynamical restraints as well as the conjugate gradient algorithm have been implemented. A large number of the normal matrix off-diagonal terms turn out to be very small and the block diagonal approximation is thus particularly efficient in the case of large structures at very high resolution.

On the application of an experimental multipolar pseudo-atom library for accurate refinement of small-molecule and protein crystal structures

With an increasing number of biomacromolecular crystal structures being measured to ultra-high resolution, it has become possible to extend to large systems experimental charge-density methods that are usually applied to small molecules. A library has been built of average multipole populations describing the electron density of chemical groups in all 20 amino acids found in proteins. The library uses the Hansen & Coppens multipolar pseudo-atom model to derive molecular electron density and electrostatic potential distributions. The library values are obtained from several small peptide or amino acid crystal structures refined against ultra-high-resolution X-ray diffraction data. The library transfer is applied automatically in the MoPro software suite to peptide and protein structures measured at atomic resolution. The transferred multipolar parameters are kept fixed while the positional and thermal parameters are refined. This enables a proper deconvolution of thermal motion and valence-electron-density redistributions, even when the diffraction data do not extend to subatomic resolution. The use of the experimental library multipolar atom model (ELMAM) also has a major impact on crystallographic structure modelling in the case of small-molecule crystals at atomic resolution. Compared to a spherical-atom model, the library transfer results in a more accurate crystal structure, notably in terms of thermal displacement parameters and bond distances involving H atoms. Upon transfer, crystallographic statistics of fit are improved, particularly free R factors, and residual electron-density maps are cleaner.

Structural basis for natural lactonase and promiscuous phosphotriesterase activities.

Organophosphates are the largest class of known insecticides, several of which are potent nerve agents. Consequently, organophosphate-degrading enzymes are of great scientific interest as bioscavengers and biodecontaminants. Recently, a hyperthermophilic phosphotriesterase (known as SsoPox), from the Archaeon Sulfolobus solfataricus, has been isolated and found to possess a very high lactonase activity. Here, we report the three-dimensional structures of SsoPox in the apo form (2.6 A resolution) and in complex with a quorum-sensing lactone mimic at 2.0 A resolution. The structure also reveals an unexpected active site topology, and a unique hydrophobic channel that perfectly accommodates the lactone substrate. Structural and mutagenesis evidence allows us to propose a mechanism for lactone hydrolysis and to refine the catalytic mechanism established for phosphotriesterases. In addition, SsoPox structures permit the correlation of experimental lactonase and phosphotriesterase activities and this strongly suggests lactonase activity as the cognate function of SsoPox. This example demonstrates that promiscuous activities probably constitute a large and efficient reservoir for the creation of novel catalytic activities.

Structure cristalline et configuration relative d'un complexe du titanocene presentant une chiralite plane et une chiralite centree sur l'atome de titane

Abstract The crystalline structure of the racemic form m.p. 164° C of the compound ( h 5 -3-MeC 5 H 3 C(Me 2 )C 6 H 5 )( h 5 -C 5 H 5 )Ti (2,6-Me 2 C 6 H 3 O)Cl has been determined by X-ray diffraction to establish the relative configuration of the two chiral moieties. This compound may be used further as a reference for studies on dynamic stereochemistry around the titanium atom. A systematic absolute nomenclature is proposed for this type of structure.

Electrostatic complementarity in an aldose reductase complex from ultra-high-resolution crystallography and first-principles calculations

The electron density and electrostatic potential in an aldose reductase holoenzyme complex have been studied by density functional theory (DFT) and diffraction methods. Aldose reductase is involved in the reduction of glucose in the polyol pathway by using NADPH as a cofactor. The ultra-high resolution of the diffraction data and the low thermal-displacement parameters of the structure allow accurate atomic positions and an experimental charge density analysis. Based on the x-ray structural data, order-N DFT calculations have been performed on subsets of up to 711 atoms in the active site of the molecule. The charge density refinement of the protein was performed with the program mopro by using the transferability principle and our database of charge density parameters built from crystallographic analyses of peptides and amino acids. Electrostatic potentials calculated from the charge density database, the preliminary experimental electron density analysis, DFT computations, and atomic charges taken from the amber software dictionary are compared. The electrostatic complementarity between the cofactor NADP+ and the active site shows up clearly. The anchoring of the inhibitor is due mainly to hydrophobic forces and to only two polar interaction sites within the enzyme cavity. The potentials calculated by x-ray and DFT techniques agree reasonably well. At the present stage of the refinement, the potentials obtained directly from the database are in excellent agreement with the experimental ones. In addition, these results demonstrate the significant contribution of electron lone pairs and of atomic polarization effects to the host and guest mechanism.