Metallothioneins (MT) are ubiquitous proteins which can interact with electrophiles including alkylating agents and gold- and platinum-dependent chemotherapeutic agents and reactive oxygen species. Crustacean MTs are useful model systems due to modifications of stoichiometry and structure. Electrostatic influences on the reactions of lobster hepatopancreas MT-1 and MT-2 with two electrophilic disulfides were investigated. 5,5’-Dithiobis-(2-nitrobenzoic acid), ESSE, and 2,2’-dithiodipyridine, PySSPy, react biphasically. Each phase has disulfide dependent and independent terms, yielding a four-term rate law : rate = k(1s)[MT] + k(2s)[RSSR][MT] + k(1f)[MT] + k(2f)[RSSR][MT]. The neutral disulfide PySSPy reacts more rapidly and has significantly greater second order rate constants than the negatively (-2) charged DTNB. The MT-1 rate constants in 5 mM Tris-HCl-100 mM KCl buffer, pH 7.4, at 25 degrees C are k(2f) = 52.5 and k(2s) = 3.65 M(-1) s(-1) for PySSPy and k(2f) = 5.80 and k(2s) = 0.70 M(-1) s(-1) for ESSE. Ionic strength studies of the reactions of ESSE and MT-1 showed a positive salt effect with increasing KCl concentration, as expected for a reaction between similarly charged species. The Debye-Huckel law, applied to k(2f) and k(2s), yielded effective charges of -1 for the two protein reaction centers. These values agree with the charges of the two domains (beta(C) and beta(N)) and support a kinetic model in which each phase of the reaction is associated with one of the domains. The reactivities are discussed in light of the novel cadmium-thiolate connectivities of the lobster MT domains.