Free Energy and Entropy from MD

Abstract

It is straightforward to predict electronic energy from QM and the potential energy from FF-based MD and more recently from QM-based MD. However, extracting entropy and free energy has been problematic. Generally, the accepted methodology, going back to Jack Kirkwood and Richard Tolman, is thermodynamic integration theory or free energy perturbation theory. These methods are rigorous for obtaining free energy differences if the perturbations are sufficiently slow that the system remains in equilibrium as system A morphs into B. This generally requires repeated equilibrium calculations during the MD, which makes it very expensive for large-scale (100,000 atom) systems. A major advance here is the validation of FEP technology by Bill Jorgensen and its implementation into an automatic module by Schodinger. To make entropy and free energy calculations practical for nanosecond reactive simulations of large systems with up to millions of atoms, Lin, Blanco, and I (LBG) developed the two-phase thermodynamics (2PT) method that is generally 1000’s of time faster than thermodynamic integration (TI) but equally accurate.