(112f) Molecular Density Functional Theory and Its Application to Hydration Free-Energy Calculations

We propose a molecular density functional theory (MDFT) as an alternative to thermodynamic integration methods in molecular simulation of solvation free energies. An analytical expression for the free-energy functional is formulated within the framework of the reference interaction site model (RISM) under the universality ansatz of the bridge functional. With the site-site direct correlation functions of pure water obtained from molecular simulation and an analytical expression for the bridge functional derived from the modified fundamental measurement theory (MFMT), MDFT enables rapid prediction of the solvation free energy using the atomic density profiles of the solvent molecules around the solute as an input. As demonstration, we show preliminary results for the hydration free-energy predictions of spherical ions, small organic molecules and amino-acid side-chain analogues. The good agreement with experimental values and/or with time-demanding molecular simulations shows that the theoretical protocol provides a computationally inexpensive alternative to thermodynamic integration methods for computation of solvation free energy and molecular recognition in aqueous solutions. Our new computational procedure is fully compatible with conventional force fields and can be easily integrated with standard simulation packages.