Crucial effect of hydration in a model for the antiepileptic vigabatrin and the prosthetic group interaction

The feasibility of a model for the first step of the interaction between th e antiepileptic VGB (gamma -vinyl GABA) and the prosthetic group PLP (pyrid oxal phosphate) is studied. In this model, CgammaH in VGB is oriented towar ds the center of the PLP ring prior to a Schiff base formation between them . Hydration is mimicked through first molecular mechanics and then molecula r dynamics, both with the Amber force field. The first hydration shell of s ix water molecules is shown to play a crucial role. Hydrogen bonds are form ed between them and (a) the carboxyl VGB group and (b) the phosphate PLP gr oup. The corresponding 3-center MO bond indices have, accordingly, signific ant values.