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Vers un potentiel multipolaire quantitatif et transférable aux macromolécules biologiques : une étude méthodologique des effets de la polarisabilité

Abstract : The goal of this work is to improve the understanding of non-covalent interactions, from the study of electron density, notably applied to protein-ligand complexes. The electron density is a relatively conserved property of atoms in similar molecular environments. This preliminary observation establishes the transferability principle. This approximation is at the root of database-based approaches, such as the ELMAM2 atom type library. This database makes it possible to reconstruct the electron density of biological molecules from fragments observed during high-resolution crystallographic experiments (and expressed in the Hansen and Coppens multipolar model). Determination of a specific type of electrostatic interaction, the interaction between induced dipole moments, profits of an innovative approach. Transferable experimental electronic densities are complemented by theoretical polarizabilities. Polarizabilities describe the response of the electron density to the application of an electric field, in order to model the classical interaction between induced dipoles. The development of new software tools, integrated into the MoProSuite software, allows several focal area presented in this manuscript. The transferability of atomic polarizabilities is discussed to evaluate their conservation between different molecular environments. Short-range interactions between molecules involve very strong electric fields. Their effect is taken into account by modelling the polarization phenomenon. The adjunction of polarization to the transferred electron density is evaluated on biological systems and small organic molecules. These transferred, then polarized, densities make it possible to calculate accurate electrostatic interaction energies, which are compared to a theoretical benchmark and an experimental case study. The study of scalar field topology, in the case of the electrostatic potential within protein-ligand complexes, is at an early stage of development. The model and the new tools developed in this thesis are steps toward the application of this approach, which describes the shape of the fields of density and electrostatic potential, to biological systems.
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Theo Leduc. Vers un potentiel multipolaire quantitatif et transférable aux macromolécules biologiques : une étude méthodologique des effets de la polarisabilité. Physique [physics]. Université de Lorraine, 2019. Français. ⟨NNT : 2019LORR0223⟩. ⟨tel-02528924⟩

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