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

Monte Carlo simulations are used to assess the adequacy of the Tanford-Kirk wood prescription for electrostatic interactions in macromolecules. Within a continuum dielectric framework, the approach accurately describes salt sc reening of electrostatic interactions for moderately charged systems consis tent with common proteins at physiological conditions. The limitations of t he Debye-Huckel theory, which forms the statistical mechanical basis for th e Tanford-Kirkwood result, become apparent for highly charged systems. It i s shown, both by an analysis of the Debye-Huckel theory and by numerical si mulations, that the difference in dielectric permittivity between macromole cule and surrounding solvent does not play a significant role for salt effe cts if the macromolecule is highly charged. By comparison to experimental d ata, the continuum dielectric model (combined with either an approximate ef fective Hamiltonian as in the Tanford-Kirkwood treatment or with exact Mont e 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.