On the calculation of free energies over Hamiltonian and order parameters via perturbation and thermodynamic integration.

In this work, complementary formulas are presented to compute free-energy differences via perturbation (FEP) methods and thermodynamic integration (TI). These formulas are derived by selecting only the most statistically significant data from the information extractable from the simulated points involved. On the one hand, commonly used FEP techniques based on overlap sampling leverage the full information contained in the overlapping macrostate probability distributions. On the other hand, conventional TI methods only use information on the first moments of those distributions, as embodied by the first derivatives of the free energy. Since the accuracy of simulation data degrades considerably for high-order moments (for FEP) or free-energy derivatives (for TI), it is proposed to consider, consistently for both methods, data up to second-order moments/derivatives. This provides a compromise between the limiting strategies embodied by common FEP and TI and leads to simple, optimized expressions to evaluate free-energy differences. The proposed formulas are validated with an analytically solvable harmonic Hamiltonian (for assessing systematic errors), an atomistic system (for computing the potential of mean force with coordinate-dependent order parameters), and a binary-component coarse-grained model (for tracing a solid-liquid phase diagram in an ensemble sampled through alchemical transformations). It is shown that the proposed FEP and TI formulas are straightforward to implement, perform similarly well, and allow robust estimation of free-energy differences even when the spacing of successive points does not guarantee them to have proper overlapping in phase space.