Charge density analysis of proteins & novel molecular recognition rules in crystals

X-ray crystallography at ultra high resolution enables to observe, beyond the atomic positions,the electron density involved in covalent bond formation within molecules. We have developed the MoPro software to determine or model the molecular electron density of small compounds and proteins [1]. The database ELMAM2 [2] was constructed to model the electron density of common chemical groups and proteins. The application on several proteins will be presented: crambin, aldose reductase [5], a phosphate transporter and cholesterol oxidase. The electron density of several oxygen atoms types show striking dissimilarities in the electron lone pairs configuration. Therefore, we have investigated the directionality and stereochemistry of hydrogen bonds with an oxygen acceptor in the Cambridge Structural Database (CSD). The results obtained through this survey are correlated with the charge density of these different chemical groups [4]. The directional attraction of hydrogen bond donors towards the lone pairs is much more pronounced for strong H-bonds. To analyze the propensity of chemical species to interact with each other, we have developed the concept of enrichment ratios [5]. The actual contact surfaces in crystal packings are compared with those computed as if all types of contacts had the same probability to form. Several series of crystals of organic compounds from the CSD were investigated using software CrystalExplorer. As expected, several polar contacts, including hydrogen bonds, show enrichment values larger than unity. Among many results, O···O, N···N and halogen···halogen contacts are under-represented while H…halogen and C…C interactions are favored. Hirshfeld, van der Waals and solvent accessible surfaces are widely usedrepresentations in protein modelling and drug design which are now available in MoProViewer software. [1] Jelsch, Guillot, Lagoutte, Lecomte, 2005, J. Appl. Cryst. 38, 38. [2] Domagala, Fournier, Liebschner, Guillot & Jelsch. Acta Cryst. A. 2012, 68, 337. [3] Fournier, Bendeif, Guillot, Podjarny, Lecomte & Jelsch. JACS. 2009, 131. 10929. [4] Ahmed, Jelsch, Guillot, Lecomte, Domagała. Crystal Growth Design. 2013. 13, 315. [5] Jelsch, Ejsmont, Huder. IUCr J. 2014. 1, 119; Jelsch, Soudani, Ben Nasr, IUCr J. 2015