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 debilitating condition phenylketonuria (PKU), which prompted research into the structure 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 (WT) PAH and how it varies with PKU-inducing mutations, Arg158Gln and Glu280Lys. We studied structures involved in a proposed mechanism for the WT and mutants using extensive mixed quantum-classical molecular dynamics simulations. Simulations reveal a previously unobserved dynamic coupling between the active site and the mutation sites, suggesting how they can affect the catalytic performance of PAH. Furthermore, the effect of the coupling on the PAH structure agrees with and expands our understanding of the experimentally observed differences in activity between the WT and mutants.