Molecular modelling at ultra high resolution

biomod_img5An extensive survey of Cambridge Structural Database is carried out to study the directionality and stereochemistry of hydrogen bonds with an oxygen acceptor including carbonyl, alcohols, phenols, ethers and esters groups. 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. Esters and ethers with the C-O-C oxygen atom located in an aromatic cycle display merged lone pairs lobes which is not the case when one of the bonded carbon atom has sp3 hybridization.

The positions of the lone pairs in the deformation electron density maps derived from theoretical calculation and from experimental charge density generally agree with the notable exception of phenols and C(sp3) esters. The experimental studies show generally lone pairs lobes which are closer to each other.

Differences are found within COH groups: the two electron lone pairs are slightly closer in phenol oxygen atoms compared to alcohols in theoretical electron densities. In experimental charge densities, the discrepancy is more drastic as the two lone pairs lobes appear merged in phenols; this might be due to a resonance effect with the neighbor sp2 carbon atom. This difference in the configuration of the two electron lone pairs affects the directionality of hydrogen bonds. For phenols, the preferred donor hydrogen atom position is close to the COH plane, while for alcohols it is out of plane with the direction O…Hdonor forming an angle of around 30° to the COH plane.

The number of H-bonds occurring with the donor hydrogen atom pointing towards the middle of the two lone pairs is small for carbonyl, contrary to alcohols and phenols. Also H-bonds involving alcohol/phenol acceptors have a stronger tendency to occur in directions close to the electron lone pairs plane than for carbonyl. As expected, the directional attraction of hydrogen bond donors towards the lone pairs is much more pronounced for short H…O distances. This study could have implications in the design of force fields, in molecular recognition, supramolecular crystal engineering and drug design.

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ELMAM2 is a generalized and improved library of experimentally derived multipolar atom types. The previously published ELMAM database is restricted mostly to protein atoms. The current database is extended to common functional groups encountered in organic molecules and is based on optimized local axes systems taking into account the local pseudosymmetry of the molecular fragment. In this approach, the symmetry-restricted multipoles have zero populations, while others take generally significant values. The various applications of the database are described. The deformation electron densities, electrostatic potentials and interaction energies calculated for several tripeptides and aromatic molecules are calculated using ELMAM2 electron-density parameters and compared with the former ELMAM database and density functional theory calculations.

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Helices represent the most abundant secondary structure motif in proteins and are often involved in various functional roles. They are stabilized by a network of hydrogen bonds between main chain carbonyl and amide groups. Several surveys scrutinized these hydrogen bonds, mostly based on the geometry of the interaction. Alternatively, the topological analysis of the electron density provides a powerful technique to investigate hydrogen bonds. For the first time, transferred experimental charge density parameters (ELMAM database) were used to carry out a topological analysis of the electron density in protein helices. New parameters for the description of the hydrogen bond geometry are proposed. Bonding contacts between the amide N and carbonyl O atoms (N 3 3 3 O) of helices, poorly addressed in the literature so far, were characterized from topological, geometrical, and local energetic analyses. Particularly, a geometrical criterion allowing for the discrimination between hydrogen bonds and N3 3 3O contacts is proposed.

Main recent references:
Elias, M, Liebschner, D., Koepke, J., Lecomte, C., Guillot, B., Jelsch C. & Chabriere E. BioMedCentral Res. Notes.2013, 6: 308. Hydrogen atoms in protein structures: high-resolution X-ray diffraction structure of the DFPase.

Bibila Mayaya Bisseyou Y, Bouhmaida N, Guillot B, Lecomte C, Lugan N, Ghermani NE & Jelsch C. Acta Cryst B. B68, 646-660. Experimental and database-transferred electron-density analysis and evaluation of electrostatic forces in coumarin-102 dye.

Poulain-Paul A, Nassour A, Jelsch C, Guillot B, Kubicki M & Lecomte C. Acta Cryst. A. (2012). A68, 715-728. A critical analysis of dipole moment calculations as obtained from experimental and theoretical structure factors.

Dadda N, Nassour A, Guillot B, Benali-Cherif N & Jelsch C. Acta Cryst. (2012). A68, 452-463. Charge-density analysis and electrostatic properties of 2-carboxy-4-methylanilinium chloride monohydrate obtained using a multipolar and a spherical-charges model

Chambrier M.H., Bouhmaida N., Bonhomme F., Lebegue S., Gillet J.M., Jelsch C. & Ghermani N.E. Crystal Growth & Design. 2011, 11, 2528–2539. Electron and Electrostatic Properties of Three Crystal Forms of Piracetam.

Liebschner D., Jelsch C., Espinosa E., Lecomte C., Chabrière E. & Guillot B. (2011) J. Phys. Chem. A, 115. 12895–12904. Topological Analysis of Hydrogen Bonds and Weak Interactions in Protein Helices via Transferred Experimental Charge Density Parameters

Paul, A., Kubicki M., Jelsch C., Durand P. & Lecomte C. (2011). Acta Cryst. (2011). B67, 365-378. R-free factor and experimental charge-density analysis of 1-(2′-aminophenyl)-2-methyl-4-nitroimidazole: a crystal structure with Z’ = 2.

Domagala S, Munshi P, Ahmed M, Guillot B & Jelsch C.* Acta Cryst. (2011). B67. 63-78. Structural analysis and multipole modelling of quercetin monohydrate – a quantitative and comparative study.

Paul A., Kubicki M., Kubas A., Jelsch C., Fink K. & Lecomte C. (2011). J. Phys. Chem. A, 115, 12941–12952. Charge Density Analysis of 2-Methyl-4-nitro-1-phenyl-1H-imidazole-5-carbonitrile: An Experimental and Theoretical Study of C≡N•••C≡N Interactions.

Liebschner D., Elias, M., Moniot, S., Fournier, B., Scott K., Jelsch, C., Guillot, B., Lecomte C. & Chabrière E. (2009). J. Am. Chem. Soc. 131, 7879–7886. Elucidation of the Phosphate Binding Mode of DING Proteins Revealed by Sub-angstrom X-ray Crystallography

Fournier B., Bendeif E.E., Guillot B., Podjarny A., Lecomte C. & Jelsch C. (2009). J. Am. Chem. Soc. 131, 10929–10941. Charge Density and Electrostatic Interactions of Fidarestat, an Inhibitor of Human Aldose Reductase

Guillot B., Jelsch C., Podjarny A. & Lecomte C. (2008) Acta Cryst. D. D64, 567-588. Charge density analysis of a protein structure at subatomic resolution: the human Aldose Reductase case.