Computing Absolute Free Energy with Deep Generative Models (2005.00638v2)

Abstract: Fast and accurate evaluation of free energy has broad applications from drug design to material engineering. Computing the absolute free energy is of particular interest since it allows the assessment of the relative stability between states without the use of intermediates. In this letter, we introduce a general framework for calculating the absolute free energy of a state. A key step of the calculation is the definition of a reference state with tractable deep generative models using locally sampled configurations. The absolute free energy of this reference state is zero by design. The free energy for the state of interest can then be determined as the difference from the reference. We applied this approach to both discrete and continuous systems and demonstrated its effectiveness. It was found that the Bennett acceptance ratio method provides more accurate and efficient free energy estimations than approximate expressions based on work. We anticipate the method presented here to be a valuable strategy for computing free energy differences.