Approches multi-échelles pour aider à clarifier les mécanismes impliqués dans les processus d'activation/inhibition de systèmes biologiques importants
Angela Parise · theses.fr (ABES) · 2022
Investigating biomolecular processes is challenging because of the intrinsic multi-scale hierarchical organization in system size and time in which chemical and chemical physical phenomena occur. Theoretical methods applied to biomolecules deals with the use of computation to obtain information about biological systems and their many interactions. The increasing accuracy of computational approaches and of computer architectures, allow to properly describe reaction paths involved in both activation/inhibition enzyme, calculate electronic properties and structural dynamics conformations of biomolecules without any limitation except those connected with the adopted theoretical protocol. Currently, computational biochemistry has predictive power and provides very insightful data that are sometimes tedious to obtain from experiment. In addition to the clarification of biochemical processes at the molecular and atomistic level, a very important application of biomolecular modeling is the guide of rational drug design process based on knowledge of a biological target (Computer-Aided Drug Design). Molecular Dynamics (MD) methods based on classical Molecular Mechanics principles have improved notions of the dynamics of molecular systems and helped to move away from the unintentional rigidity imposed by crystallographic structural determination. Density Functional Theory (DFT) is a widely used theoretical method for carrying out quantum calculations in chemistry and biology research. With DFT, chemical processes involving electron reorganization such as charge transfer or formation/cleavage of covalent bonds can addressed in more reasonable computation times than a few decades ago. Nowadays, systems encompassing up to thousands of atoms are amenable to computer simulations. Hybrid quantum/classical methods (QM/MM) are used for modeling large molecular systems. In this way, a smaller region of a larger system is treated with the most accurate QM methods, while environmental contributions are still accounted with simpler and faster MM calculations. The objective of this PhD thesis is to elucidate activation or inhibition mechanisms involved in enzyme activity by using multiscale and original computational approaches.