Effects of the solute model and concentration on the calculated free energy of hydration in explicit solvent solution

Effects of the atom model and the atomic charge parameters on the calculated free energy of hydration (FEH) have been studied for CH3OH, CH3NH2, CH3CN, and N(CH3)(3) with the all-atom vs the united-atom model for the CH3 group. Monte Carlo simulations using the free energy perturbation method have been performed in a TIP4P water box at T = 298 and p = 1 atm. Different sets of charge parameters obtained by fits to the gas-phase and in-solution B3LYP/6-31G* molecular electrostatic potentials (ELPO) and to the in-solution B3LYP/6-311++G** ELPO have been applied. Calculations with OPLS and RESP charges have been also completed. FEH values were calculated by charge and volume annihilations and developments. Volume development has also been studied for aniline, using the all-atom approach with explicit C-H atoms. For considering the concentration effect on the calculated standard free energy in solution, the (CH3OH)(2), (CH3NH2)(2), and (CH3CN)(2) dimers, and the (CH3NH2)(9) ninemer have been studied in aqueous solution at about 1 mol/dm(3) concentration. Radial distribution and pair-energy distribution functions for the monomer and ninemer have been compared to point out structural changes in the solution around a solute, caused by the presence of other solutes in the system. Using the all-atom instead of the united-atom model, the electrostatic part of the free energy of hydration becomes more negative by 0.8-3.0 kcal/mol for the four molecules in infinitely dilute solution. The increase in the van der Waals free energy term is up to 1 kcal/mol. Calculated values for the total free energy of hydration considerably depends on the accepted charge set and steric parameters for the solute in the all-atom model. No remarkable dependence on the solute concentration has been found for the electrostatic free energy of hydration; thus the technically simpler estimation of the total standard free energy of solvation based on simulations for infinitely dilute solutions is acceptable.