Alchemical free energy simulations without speed limits. A generic framework to calculate free energy differences independent of the underlying molecular dynamics program

We describe the theory of the so-called common-core/serial-atom-insertion (CC/SAI) approach to compute alchemical free energy differences and its practical implementation in a Python package called Transformato. CC/SAI is not tied to a specific biomolecular simulation program and does not rely on special purpose code for alchemical transformations. To calculate the alchemical free energy difference between several small molecules, the physical end-states are mutated into a suitable common core. Since this only requires turning off interactions, the setup of intermediate states is straightforward to automate. Transformato currently supports CHARMM and OpenMM as back ends to carry out the necessary molecular dynamics simulations, as well as post-processing calculations. We validate the method by computing a series of relative solvation free energy differences.

Automated summary

The common-core/serial-atom-insertion (CC/SAI) approach is presented for computing alchemical free energy differences between small molecules by mutating physical end-states into a suitable common core. This method, implemented in the Python package Transformato, does not require special purpose code and can be easily automated for setting up intermediate states. The method is validated by calculating relative solvation free energy differences.