Consider two systems, A and B, with potential energies ${\displaystyle U_{A}}$  and ${\displaystyle U_{B}}$ . The potential energy in either system can be calculated as an ensemble average over configurations sampled from a molecular dynamics or Monte Carlo simulation with proper Boltzmann weighting. Now consider a new potential energy function defined as:

${\displaystyle U(\lambda )=U_{A}+\lambda (U_{B}-U_{A})}$ 

Here, ${\displaystyle \lambda }$  is defined as a coupling parameter with a value between 0 and 1, and thus the potential energy as a function of ${\displaystyle \lambda }$  varies from the energy of system A for ${\displaystyle \lambda =0}$  and system B for ${\displaystyle \lambda =1}$ . In the canonical ensemble, the partition function of the system can be written as:

${\displaystyle Q(N,V,T,\lambda )=\sum _{s}\exp[-U_{s}(\lambda )/k_{B}T]}$ 

In this notation, ${\displaystyle U_{s}(\lambda )}$  is the potential energy of state ${\displaystyle s}$  in the ensemble with potential energy function ${\displaystyle U(\lambda )}$  as defined above. The free energy of this system is defined as:

${\displaystyle F(N,V,T,\lambda )=-k_{B}T\ln Q(N,V,T,\lambda )}$ ,

If we take the derivative of F with respect to λ, we will get that it equals the ensemble average of the derivative of potential energy with respect to λ.

${\displaystyle {\begin{aligned}\Delta F(A\rightarrow B)&=\int _{0}^{1}{\frac {\partial F(\lambda )}{\partial \lambda }}d\lambda \\&=-\int _{0}^{1}{\frac {k_{B}T}{Q}}{\frac {\partial Q}{\partial \lambda }}d\lambda \\&=\int _{0}^{1}{\frac {k_{B}T}{Q}}\sum _{s}{\frac {1}{k_{B}T}}\exp[-U_{s}(\lambda )/k_{B}T]{\frac {\partial U_{s}(\lambda )}{\partial \lambda }}d\lambda \\&=\int _{0}^{1}\left\langle {\frac {\partial U(\lambda )}{\partial \lambda }}\right\rangle _{\lambda }d\lambda \\&=\int _{0}^{1}\left\langle U_{B}(\lambda )-U_{A}(\lambda )\right\rangle _{\lambda }d\lambda \end{aligned}}}$ 

The change in free energy between states A and B can thus be computed from the integral of the ensemble averaged derivatives of potential energy over the coupling parameter ${\displaystyle \lambda }$ .^[2] In practice, this is performed by defining a potential energy function ${\displaystyle U(\lambda )}$ , sampling the ensemble of equilibrium configurations at a series of ${\displaystyle \lambda }$  values, calculating the ensemble-averaged derivative of ${\displaystyle U(\lambda )}$  with respect to ${\displaystyle \lambda }$  at each ${\displaystyle \lambda }$  value, and finally computing the integral over the ensemble-averaged derivatives.

Umbrella sampling is a related free energy method. It adds a bias to the potential energy. In the limit of an infinite strong bias it is equivalent to thermodynamic integration.^[3]

• Free energy perturbation
• Bennett acceptance ratio
• Parallel tempering
• Alchemy