Thermodynamic integration

Thermodynamic integration is a method used to compare the difference in free energy between two given states (e.g., A and B) whose potential energies $U_{A}$ and $U_{B}$ have different dependences on the spatial coordinates. Because the free energy of a system is not simply a function of the phase space coordinates of the system, but is instead a function of the Boltzmann-weighted integral over phase space (i.e. partition function), the free energy difference between two states cannot be calculated directly. In thermodynamic integration, the free energy difference is calculated by defining a thermodynamic path between the states and integrating over ensemble-averaged enthalpy changes along the path. Such paths can either be real chemical processes or alchemical processes. An example alchemical process is the Kirkwood's coupling parameter method.^[1]

Derivation

Consider two systems, A and B, with potential energies $U_{A}$ and $U_{B}$ . 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:

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

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

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

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

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.

\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

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 $\lambda$ .^[2] In practice, this is performed by defining a potential energy function $U(\lambda )$ , sampling the ensemble of equilibrium configurations at a series of $\lambda$ values, calculating the ensemble-averaged derivative of $U(\lambda )$ with respect to $\lambda$ at each $\lambda$ 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]

References

↑ J. G. Kirkwood. Statistical mechanics of fluid mixtures, J. Chem. Phys., 3:300-313,1935
↑ Frenkel, Daan and Smit, Berend. Understanding Molecular Simulation: From Algorithms to Applications. Academic Press, 2007
↑ J Kästner; et al. (2006). "QM/MM Free-Energy Perturbation Compared to Thermodynamic Integration and Umbrella Sampling: Application to an Enzymatic Reaction". JCTC. 2 (2): 452–461. doi:10.1021/ct050252w.

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Thermodynamic integration

Derivation

See also

References