A two-step method for the evaluation of free energy of formation for subnanometer cavities.

An original two-level scheme for the calculation of free energy of formation for cavities of various volume and shape in water by the method of thermodynamic integration. Statistical integrals are calculated with use of Monte Carlo sampling an ensemble of water molecules with periodic boundary conditions. An implementation of the proposed scheme is carried out in CAVE (CAVity free Energy) program. In order to determine the optimum parameters for modeling with the algorithm, some test computations for a sphere and for several organic molecules of small and average size were performed. The interaction between water molecules is described within the TIP4P water model. To test the CAVE program, a set of thermodynamic values of the TIP4P water model was computed. All the found values are in good agreement with the results known from the literature.