Monte Carlo simulations of the counter ion effect on the conformational equilibrium of the N , N ′-diphenyl-guanidinium ion in aqueous solution

Results of calculations for the equilibrium of the syn–syn, anti–syn, and anti–anti conformers of the N, N′-diphenyl-guanidinium ion in aqueous solution are sensitive to whether a counter ion is considered. Relative internal free energies were calculated upon MP2/6-31G*//HF/4-31G energies (second order Mo/ller–Plesset energies obtained when using the 6-31G* basis set at geometries optimized at the Hartree–Fock level and using the 4-31G basis set) and relative solvation free energy terms were obtained by Monte Carlo simulations. Without considering a counter ion only a small fraction of the solute has been predicted to adopt the anti–anti conformation in the solution. When considering acetate and chloride counter ions with salt concentration of 0.11 mol/ℓ at 310 K, mimicking physiological conditions, the counter ion close to the cation stabilizes the anti–anti form significantly. Though there are not local free energy minima for the present systems with close counter ions because of the relatively weak ion–ion interaction due to the largely delocalized total charge and atomic charge alternation in the cation, the constraint for the C(guanidinium)...C(carboxylate) separation of 4.6 Å allows an insight into the arginine...aspartate or glutamate interactions commonly found in peptides. The N–H(guanidinium)...O(carboxylate) hydrogen bonds are not stable due to thermal motion in aqueous solution. The neighboring water molecules, however, move into the space in-between the charged groups and comprise a hydrogen bonded network. Interactions with a chloride counter ion may be significant for the drug delivery process to the receptor site. Close contact between the N, N′-diphenyl guanidinium and a chloride ion is also not favored, though it may occur temporarily and then would favor the anti–anti conformer. Deviation from the relative solvation free energy obtained for the conformational change of the single cation is still some tenths of a kcal/mol with ions separated as much as 12.4 Å. While solvation energetics is affected even at such a separation, solution structure around the ions can be basically characterized without considering the effect of a remote counterpart.