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Cristallographie à ultra haute résolution et analyse expérimentale des énergies d'interaction intermoléculaires

Abstract : The electrostatic properties are of major importance in many biological processes (catalysis, molecular recognition, ligand affinity) and in the crystal packing formation of small molecules. The calculation of the electrostatic interaction energy between a protein and a ligand allows the analysis of the structure/function relationships of the protein. A precise description of the electron density of the studied molecules is then necessary. This can be obtained by using an aspherical atom model, like the multipolar model of Hansen & Coppens, refined from X-ray diffraction data at ultra high resolution. In order to calculate the electrostatic contribution of the interaction energy, advanced methods of numerical integration were implemented in the VMoPro software. To analyze the various electrostatic properties, the program was modernized and developed: 2D and 3D grids calculations, atom selection, Fourier synthesis, Laplacian and critical point analysis, electrostatic potential, van der Waals energy and electrostatic interaction energy. Tests of precision were made to validate the integration method and to carry out the first applications in a urea crystal. The methodology is currently applied to the calculation of the interactions between the human aldose reductase protein and the Fidarestat ligand. The experimental charge densities of two nucleic acids bases (ribonucleotide thymidine and cytosine) were analyzed to extend the multipolar atom databank describing the electron density of biomolecules.
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Angélique Lagoutte. Cristallographie à ultra haute résolution et analyse expérimentale des énergies d'interaction intermoléculaires. Autre. Université Henri Poincaré - Nancy 1, 2007. Français. ⟨NNT : 2007NAN10143⟩. ⟨tel-01754263⟩



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