Modelling copper-containing proteins

Abstract

To be able to perform Molecular Dynamics (MD) simulations of proteins, a model is needed to describe the interactions between the atoms witin the protein. The interactions between a metal-ion, in this case copper, and a ligand can vary strongly so that a standard set can not be used. This thesis describes the development of a non-bonded and a covalently bonded force field for the copper-site by using an empirically resp. quantum chemically derived charge distribution. The force fields were applied on several instances. 1) It appears that the possible involvement of a mobile loop after substrate binding to the copper-containing quercetinase may help keeping the substrate in place. 2) It turns out that the thermodynamic integration method only allows qualitative predictions of the variation in redox potential observed for azurin variants. 3) The dynamics of the hydrophobic core of azurin variants were analysed in light of previous time dependent phosphorescence experiments. They stress the importance of charge and dipole variations of the surroundings of the tryptophane in the structure for its phosphorescence properties. 4) Finally MD simulations show that a loop, carrying an engineered cysteine, is able to undergo a large conformational change enabling to co-ordinate the copper site of azurin.