Uncovered Dynamic Coupling Resolves the Ambiguous Mechanism of Phenylalanine Hydroxylase Oxygen Binding

Phenylalanine hydroxylase (PAH) is an iron enzyme catalyzing the oxidation of L-Phe to L-Tyr during phenylalanine catabolism. Dysfunction of PAH leads to the de- bilitating condition phenylketonuria (PKU), which prompted research into the struc- ture and function of PAH over the last 50 years. Despite intensive study, there is no consensus on the atomistic details of the mechanism of O2 binding and splitting by wild type PAH and how it varies with PKU-inducing mutations, Arg158Gln and Glu280Lys. We studied structures involved in a proposed mechanism for the wild type and mutants using extensive mixed quantum-classical molecular dynamics simulations. Simulations reveal a previously unobserved dynamic coupling between active site and the mutation sites, suggesting how they can aect the catalytic performance of PAH. Furthermore, the eect of the coupling on PAH structure agrees with and expands our understanding of the experimentally observed dierences in activity between the wild type and mutants.