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 aque ous solution are sensitive to whether a counter ion is considered. Rel ative internal free energies were calculated upon MP2/6-31G//HF/4-31G energies (second order Moller-Plesset energies obtained when using th e 6-31G basis set at geometries optimized at the Hartree-Fock level a nd using the 4-31G basis set) and relative solvation free energy terms were obtained by Monte Carlo simulations. Without considering a count er 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 c ation stabilizes the anti-anti form significantly. Though there are no t local free energy minima for the present systems with close counter ions because of the relatively weak ion-ion interaction due to the lar gely delocalized total charge and atomic charge alternation in the cat ion, the constraint for the C(guanidinium)... C(carboxylate) separatio n of 4.6 Angstrom allows an insight into the arginine aspartate or glu tamate interactions commonly found in peptides. The N-H(guanidinium).. . O(carboxylate) hydrogen bonds are not stable due to thermal motion i n aqueous solution. The neighboring water molecules, however, move int o the space in-between the charged groups and comprise a hydrogen bond ed network. Interactions with a chloride counter ion may be significan t for the drug delivery process to the receptor site. Close contact be tween the N, N'-diphenyl guanidinium and a chloride ion is also not fa vored, though it may occur temporarily and then would favor the anti-a nti conformer. Deviation from the relative solvation free energy obtai ned for the conformational change of the single cation is still some t enths of a kcal/mol with ions separated as much as 12.4 Angstrom. Whil e solvation energetics is affected even at such a separation, solution structure around the ions can be basically characterized without cons idering the effect of a remote counterpart. (C) 1996 American Institut e of Physics.