The biosynthesis of serotonin requires aromatic substrates to be bound in the active sites of the enzymes tryptophan hydroxylase and aromatic amino acid decarboxylase. These aromatic substrates are held in place partially by dispersion and induction interactions with the enzymes' aromatic amino acid residues. Mutations that decrease substrate binding can result in a decrease in serotonin production and thus can lead to depression and related disorders. We use optimized crystal structures of these two enzymes to examine pair-wise electronic interaction energies between aromatic residues in the active sites and the aromatic ligands. We also perform in silico mutations on the aromatic residues to determine the change in interaction energies as mutations occur. Our second-order Moller-Plessett perturbation theory calculations show that drastic changes in interaction energy can occur and, in light of our previous work, we are able to use these data to offer predictions on the loss of protein function and on the possibility of disease upon mutation. We also examine local and gradient corrected density functional theory methods to evaluate their ability to predict these induction/dispersion-dominated interaction energies. We find that the hybrid B3LYP cannot model these interactions well, whereas the GGA HCTH407 offers largely qualitatively correct results, and the local functional SVWN quantitatively mimics the MP2 results rather well.
2008 Wiley Periodicals, Inc.