In this paper an EVB-based method to describe the energetics of operation of arbitrary-length heterogeneous proton-wires is described. The method keeps the number of fittable parameters low by exploiting the idea of "protonation states". The method is applied to describe the 3-proton proton-wire described in Green Fluorescent Protein (GFP), and two sets of parameters have been obtained, one for the electronic ground state and another for the photoactive excited electronic state, of a chemical model including the groups supporting the proton-wire and based on CASPT2//CASSCF quality reference energies. The fitted EVB functions are analyzed in static terms. In this way, it is seen that only a minimum exists in S0while two exist in S 1: one for the photoproduct and one for the reactant in the excited state, even though consideration of the Franck-Condon excitation energy predicts an effective barrier under 1 kcal mol-1. Topological analysis of the transition state structure reveals a concerted but asynchronous motion of the protons, where the chromophore's proton lags behind, and the final proton of the wire that goes from Ser205 to Glu222 leads the process. Inclusion of nuclear dynamic efects causes this small effective barrier to vanish and predicts an essentially barrierless process in the excited state. © 2008 American Chemical Society.