Conformational dependence of serotonin theoretical pKa prediction

In the present work we used quantum mechanics calculations to predict the two pKa's of 5-hydrotryptamine (5-HT). Proton dissociation reaction succeeded to predict the experimental pKa1 corresponding to ionization of the protonated amine group but failed for pKa2 corresponding to ionization of the 5-hydroxyl group. For pKa2, a cluster-continuum model including three water molecules in the first hydration shell around 5-hydroxyl and 5-hydroxide groups enabled us to reproduce the experimental pKa2 value. Furthermore, we demonstrated that specific conformations of acid/base pair of 5-HT is critical to predict accurately the experimental pKa's of the flexible 5-HT molecule.