QM/MM methods: looking inside heme proteins biochemistry

Mixed quantum mechanics/molecular mechanics methods offer a valuable computational tool for understanding biochemical events. When combined with conformational sampling techniques, they allow for an exhaustive exploration of the enzymatic mechanism. Heme proteins are ubiquitous and essential for every organism. In this review we summarize our efforts towards the understanding of heme biochemistry. We present: 1) results on ligand migration on globins coupled to the ligand binding event, 2) results on the localization of the spin density in compound I of cytochromes and peroxidases, 3) novel methodologies for mapping the electron transfer pathways and 4) novel data on Tryptophan 2,3-dioxygenase. For this enzyme our results strongly indicate that the distal oxygen will end up on the C3 indole carbon, whereas the proximal oxygen will end up in the C2 position. Interestingly, the process involves the formation of an epoxide and a heme ferryl intermediate. The overall energy profile indicates an energy barrier of approximately 18 kcal/mol and an exothermic driving force of almost 80 kcal/mol.