Objective X-ray crystallography at ultra-high resolution enables to observe the deformation of the atomic electron densities due to chemical bonding and intermolecular interactions. These can be quantitatively analysed via charge density studies, a mature and dynamic branch of modern crystallography, which provides important chemical information (charges, bond order, nucleophilicity…) on the atoms. For the analysis of the increasing number of protein structures measured at subatomic resolution, LCM3B has developed the program MoPro and a multipolar library describing the electron density of atoms. The laboratory has pioneered in extending these methodologies from small molecules to proteins with the multipolar refinement of crambin and human aldose reductase. The excellent quality diffraction data collected for aldose reductase, an enzyme involved in diabetes complications, will allow further unprecedented analysis of the electron density in alpha-helices and beta-strands. Preliminary results demonstrate the feasibility of the crystallographic refinement as the polypeptide main-chain groups C=O…H-N show significant differences in atoms polarization. These will be quantified experimentally with software MoPro and confirmed by quantum chemical computations. The strong background of the applicant in quantum chemistry will be advantageous to analyse the relationships between atoms polarization, helix macro-dipole and hydrogen bonding geometry and strength in proteins. In the second phase of the project, it is aimed to improve the accuracy of electrostatic interaction energies computed on protein-substrate systems by using a multipolar atom model compared to point charges. The structures of complexes of human aldose reductase with several medicinal inhibitors are determined at high resolution. The electron density will be transferred from our library of multipolar atoms. This will allow analysing the ligands binding strength and the specificity with respect to the proteins. Fields of science natural sciencescomputer and information sciencessoftwarenatural sciencesearth and related environmental sciencesgeologymineralogycrystallographynatural scienceschemical sciencesphysical chemistryquantum chemistrynatural sciencesmathematicspure mathematicsgeometrynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Keywords Electron Protein structure Quantum chemistry Structural biology X-ray Crystallography Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) PEOPLE-2007-4-2.IIF - Marie Curie Action: "International Incoming Fellowships" Call for proposal FP7-PEOPLE-2007-4-2-IIF See other projects for this call Funding Scheme MC-IIF - International Incoming Fellowships (IIF) Coordinator CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS EU contribution € 173 301,94 Address RUE MICHEL ANGE 3 75794 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Administrative Contact Michel Mauvais (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
