Études de systèmes organométalliques et biologiques par des méthodes hybrides mécanique quantique/mécanique moléculaire

par Marius Retegan

Thèse de doctorat en Chimie physique, moléculaire et structurale

Sous la direction de Anne Milet et de Hélène Jamet.

Soutenue en 2009

à l'Université Joseph Fourier (Grenoble ; 1971-2015) .

mots clés

• Théorie quantique
• Composés organométalliques

Résumé

Ces dernières années, les méthodes hybrides QM/MM combinant la mécanique quantique (QM) et la mécanique moléculaire (MM) se sont revélées des méthodes de choix pour l'étude de systèmes chimiques et biochimiques contenant plus d'une centaine d'atomes. Nous avons mis en évidence les apports et difficultés liés à leur utilisation à travers des systèmes variés: modélisation de ligands phosphines, réactivité d'une protéine de type acide phosphatase pourpre, modélisation de l'interaction protéine-ligand.

Titre traduit

Studies of organometallic and biological systems by hybrid quantum mechanics/molecular mechanics methods

Résumé

In the recent years the hybrid QM/MM methods, which combine the quantum mechanics (QM) with molecular mechanics (MM), have emerged as a promising route for studying complex biological and chemical systems containing more than a few hundreds atoms. In the present manuscript we showed their advantages and shortcomings in studying various problems, ragging from the modelization of phosphine ligands, enzymatic reactivity of the purple acid phosphatase and the modelization of protein-ligand interaction between the casein kinase 2 protein and its inhibitors.

Résumé

Ln the recent years the hybrid QM/MM methods, which combine the quantum mechanics (QM) with molecular mechanics (MM), have emerged as a promising route for studying complex biological and chemical systems containing more than a few hundreds atoms. Ln the present manu script we showed their advantages and short-comings in studying various problems, ragging from the modelization ofphosphine ligands, enzymatic reactivity of the purple acid phosphatase and the modelization of protein-ligand interaction between the casein kinase 2 protein and its inhibitors. The first study has allowed us to evaluate how the position of the QM-MM borderinfluences the electronic structure and the geometrical parameters of the phosphine ligands commonly used in the Pauson-Khand reaction. Subsequently, the influence of the protein environment on the reactivity of purple acid phosphatase was studied by employing a QM/MM method. Finally, in the last study, we proposed an original methodology for description of the interaction energy between a protein and an inhibitor. The method was tested and validated on different inhibitors of the casein kinase 2 protein. This allowed us to explain the results obtained by a virtual screening of the DCM chemicallibrary.