Computer Simulation of Chemical Reactivity of Heme Proteins

Abstract

We present an investigation of the molecular basis of chemical reactivity modulation in selected heme proteins using a combination of classical molecular dynamics and hybrid quantum-classical (QM-MM) simulations. Results will be presented for: i) Tryptophane and indoleamine dioxygenases, two related heme proteins of physiological relevance that catalyze the oxidative ring cleavage reaction of L-tryptophan to N-formyl kynurenine. We will show the molecular basis of the different selectivity of these proteins, and a detailed analysis of the reaction mechanism, which shows that the 2 atoms of dioxygen are inserted into the substrate via a consecutive 2 step reaction. ii) Analysis of the molecular basis of hexacoordination in human neuroglobin. Our results suggest that protein oxidation through the formation of a disulfide bridge promotes the stabilization of the pentacoordinated species, thus favoring the reactive state and suggesting a O2 storage function for neuroglobin. Results obtained using high pressure simulations of neuroglobin and myoglobin suggest that the equilibrium between the 5c and the 6c states in globins is largely controlled by the structure and dynamics of the CD region.