Salt-bridge formation between Asp/Glu center dot center dot center dot Lys and Asp/Glu center dot center dot center dot Arg side chains has been studied by model systems including formic and acetic acids as proton donors and methylamine, guanidine, and methylguanidine as proton acceptors. Calculations have been performed up to the CCSD(T)(cBs)//MP2/aug-cc-pvtz level with formic acid proton donors. Complexes formed with acetic acid were studied at the CCSINT)/aug-cc-pvdz// MP2/aug-cc-pvdz level. Protein environments of low and moderate polarity were mimicked by a continuum solvent with dielectric constants (epsilon) set to 5 and 15, respectively. Free energy differences, Delta G(tot), were calculated for the neutral, hydrogen-bonded form and for the tautomeric ion pair. These values predict that a salt bridge is not favored for the Asp/Glu center dot center dot center dot Lys pair, even in an environment with epsilon as large as 15. In contrast, the Asp/Glu center dot center dot center dot Arg salt bridge is feasible even in an environment with epsilon = 5. Charge transfers for the complexes were calculated on the basis of CHELPG and AIM charges.