Calculation of molecular complexation free energy by thermodynamic integration with harmonic restrictions on atomic coordinates

A new method for calculating the Gibbs free energy of intermolecular complex formation using the thermodynamic integration method with harmonic restrictions on atomic coordinates is proposed. The molecular dynamic trajectory for the thermodynamic integration is obtained using the MMFF94 force filed for calculating the energy of interaction between atoms. It is shown that the method provides the correct calculation of the free energy term from the harmonic restriction and minimizes the fluctuations during the integration procedure. The free energy for benzene-cyclodextrine host-guest complex formation is determined.