MoProViewer: a tool to study proteins from a charge density science perspective

Applying the charge density science methods to the structural biology field remains a considerable challenge. Several approaches were followed in the past years, focusing either on multipolar refinement of the rare available subatomic resolution protein structures or on the application of the transferability principle for the evaluation of electrostatic and energetic properties in protein-ligand complexes. However, the usually large size of macromolecules and the consequently large number of multipolar parameters in the Hansen & Coppens formalism [1] obviously complicates the feasibility of such kind of studies. In this presentation, we introduce the tools implemented in the MoProViewer software, part of the MoPro Suite for charge density refinement, especially designed to ease the analysis of a protein structure from a charge density perspective. These tools focus on helping the user in the computation of properties deriving from a refined or transferred [2] protein charge distribution and to manage a large number of atoms described in the multipole formalism in terms for instance of atomic local axis, symmetry or chemical equivalences constraints definitions. Moreover we will present new methods based on the topological analysis of the electrostatic potential [3]. They are designed to allow an original use of the electrostatic properties of a protein-ligand complex structure and rely on the computation and the representation of electrophilic and nucleophilic influence zones of atoms involved in protein-ligand interactions or in a biochemical process. The computational details of these methods as well as application examples on selected protein-ligand complexes will be given.

Charge-density analysis and electrostatic properties of a new hybrid compound

2-carboxy-4-methylaniline is a biologically active molecule serving as a pharmaceutical intermediate [1]. We've synthesized, studied and refined the crystal structure of its derivative 2-carboxy-4-methylanilinium chloride monohydrate using three different electron-density models. In the first model, the ELMAM2 multipolar electron-density database [2] was transferred to the molecule. Theoretical structure factors were also computed from periodic density functional theory calculations [3] and yielded, after multipolar-atoms refinement, the second charge-density model. An alternative electron-density modelling, based on spherical atoms and additional charges on the covalent bonds and electron lone-pair sites, was used in the third model in the refinement versus the theoretical data. The crystallographic refinements, structural properties, electron-density distributions and molecular electrostatic potentials obtained from the different charge-density models were compared.

Molecular recognition enrichment rules in crystals and protein/ligand complexes

To analyze the propensity of chemical species to interact with each other, we have developed the concept of enrichment ratios. The ratios are derived from the decomposition of the contact surface between pairs of interacting chemical species. The actual contacts are compared with those computed as if all types of contacts had the same probability to form. As expected, several polar contacts, which can be hydrogen bonds and show electrostatic complementarity, show enrichment values larger than unity. Among other results, O···O and N···N contacts are impoverished while H···H interactions appear very slightly disfavored. We have also investigated the directionality and stereochemistry of hydrogen bonds with an oxygen acceptor including in the Cambridge Structural Database [1]. The results obtained through this survey are correlated with the charge density of these different chemical groups. The electron density of these different oxygen atoms types show striking dissimilarities in the electron lone pairs configuration. As previously observed, the directional attraction of hydrogen bond donors towards the lone pairs is much more pronounced for strong H-bonds. Van der Waals and solvent accessible surfaces are widely used representations in protein modelling and drug design. We propose in the software MoproViewer [2] a revisited definition of the molecular surface based on flattened atoms when strong hydrogen bonding is possible. These stereochemical relationships found in molecular recognition within crystal structures of small compounds have implications in drug design and were investigated in some protein/ligand cases. Finally protein/ligand electrostatic calculations are compared using two different charge density models: multipoles vs spherical dummy charges on bonds and lone pairs[3].