Accuracy Test of the OPLS-AA Force Field for Calculating Free Energies of Mixing and Comparison with PAC-MAC

[Image: see text] We have calculated the excess free energy of mixing of 1053 binary mixtures with the OPLS-AA force field using two different methods: thermodynamic integration (TI) of molecular dynamics simulations and the Pair Configuration to Molecular Activity Coefficient (PAC-MAC) method. PAC-MAC is a force field based quasi-chemical method for predicting miscibility properties of various binary mixtures. The TI calculations yield a root mean squared error (RMSE) compared to experimental data of 0.132 k(B)T (0.37 kJ/mol). PAC-MAC shows a RMSE of 0.151 k(B)T with a calculation speed being potentially 1.0 × 10(4) times greater than TI. OPLS-AA force field parameters are optimized using PAC-MAC based on vapor–liquid equilibrium data, instead of enthalpies of vaporization or densities. The RMSE of PAC-MAC is reduced to 0.099 k(B)T by optimizing 50 force field parameters. The resulting OPLS-PM force field has a comparable accuracy as the OPLS-AA force field in the calculation of mixing free energies using TI.