Molecular Dynamics Simulations and Free Energy Calculations of HemQ Proteins

HemQ proteins are a novel discovered class of proteins that play an important role in the heme biosynthetic pathway in Firmicutes and Actinobacteria. HemQ catalyzes two consecutive oxidative decarboxylations of coproheme molecule, cleaving off two propionate groups to yield heme b, following a reaction that is not yet known. The coproheme demonstrates a high binding affinity toward HemQ, with an extremely fast binding rate, whereas heme b is bound less tightly. This suggests a possible reaction mechanism, where the coproheme released by the HemH enzyme is immediately bound by HemQ, which then catalyzes the decarboxylation of propionates in position 2 (p2) and 4 (p4) of the porphyrin ring to form the respective vinyl groups. The heme b molecule thus formed is then released due to its lower binding affinity, probably caused by the decreased non-bonded interactions with the protein after the two propionates have been cleaved off. However the reaction mechanism is poorly understood. Molecular dynamics simulations and free energy calculations are used to better understand the dynamics of this protein and the reaction it catalyzes. Typical analysis are performed to study the structural behavior of this protein, while free energy calculations are conducted using two different approaches: the thermodynamic integration (TI) and the Linear Interaction Energy (LIE) method.