Conformational dependence of serotonin theoretical pKa prediction

In the present work we used quantum mechanics calculations to predict the two pK(a)'s of 5-hydrotryptamine (5-HT). Proton dissociation reaction succeeded to predict the experimental pK(a1) corresponding to ionization of the protonated amine group but failed for pK(a2) corresponding to ionization of the 5-hydroxyl group. For pK(a2), 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 pK(a2) value. Furthermore, we demonstrated that specific conformations of acid/base pair of 5-HT is critical to predict accurately the experimental pK(a)'s of the flexible 5-HT molecule. (c) 2006 Elsevier B.V. All rights reserved.