Free Energy Methods

In this lecture, we will consider aspects of computing free energy differences from molecular simulations. The umbrella terms “free-energy methods” or “free-energy calculations” cover a wide and growing array of methods for computing free energies [42]. Some, like the Widom test-particle insertion method and metadynamics, can be computed using a single simulation, while others require a series of simulations that carefully span the space between metastable states. In some cases, that space is an artificial mixture of two Hamiltonians, as in classical thermodynamics integration (TI), or it is a region of “feature space” for a single Hamiltonian that separates two actual metastable states, as in potential of mean force (PMF) calculations. In these remaining sections, we will touch on a few of these methods.