A critical investigation of the Tanford-Kirkwood shceme by means of Monte Carlo simulations

Monte Carlo simulations are used to assess the adequacy of the Tanford-Kirkwood prescription for electrostatic interactions in macromolecules. Within a continuum dielectric framework, the approach accurately describes salt screening of electrostatic interactions for moderately charged systems consistent with common proteins at physiological conditions. The limitations of the Debye-Huckel theory, which forms the statistical mechanical basis for the Tanford-Kirkwood result, become apparent for highly charged systems. It is shown, both by an analysis of the Debye-Huckel theory and by numerical simulations, that the difference in dielectric permittivity between macromolecule and surrounding solvent does not play a significant role for salt effects if the macromolecule is highly charged. By comparison to experimental data, the continuum dielectric model (combined with either an approximate effective Hamiltonian as in the Tanford-Kirkwood treatment or with exact Monte Carlo simulations) satisfactorily predicts the effects of charge mutation on metal ion binding constants, but only if the macromolecule and solvent are assigned the same or similar permittivities.