Simulating biochemical physics with computers

Abstract

This dissertation is composed of three parts. The first part is to argue the solvent effects on the solvatochromic shift of the n ! !* excitation of acetone in ambient and supercritical water fluid using a hybrid QM!CI/MM potential in MC simulations. The solute is described by the AM1 approach and water molecules are treated classically. Specially, the spontaneous polarization of the solvent due to the excitation of the solute was considered. The solvent effects on the blue shift of acetone in water fluids at various temperatures and solvent densities are examined. The second part is to investigate the role of dopa decarboxylase (DDC) in the catalysis of converting anti-Parkinson drug L-dopa into dopamine. By means of combined QM/MM potentials in MD simulations, we first analyze the factors contributing to the tautomeric equilibrium of an intramolecular proton transfer in the external PLP!L-dopa aldimine (the Michaelis complex). How the intrinsic properties, solvent effects as well as the enzyme environment control the shift of the equilibrium is discussed. Afterward, the free energy profiles for the decarboxylations of the external aldimines both in water and in DDC are calculated. The contributions of DDC to the rate enhancement of the reaction are elucidated. The reaction mechanism of L-dopa decarboxylation in DDC is proposed. The third part is to study the structural dynamics of lysine-specific demethylase (LSD1) in complex with CoREST and protein-substrate interactions of LSD1 with histone H3 tail. MD simulations of LSD1•CoREST complex bound to a 16 a.a. of the Nterminal H3-tail peptide (H3-p16) were carried out using NAMD to study the conformational flexibility of the protein complex, especially the substantial oscillation of the TOWER domain. In addition, the simulations reveal some important protein-peptide and peptide-peptide interactions between LSD1 and H3-p16 that are absent in the crystal structure.