Alchemical free energy calculations are increasingly being used for structure based rational drug design. In this work we introduce the multiple-PSF methodology implemented in the CHARMM GPU molecular dynamics package which allows the usage of Enveloping Distribution Sampling, Thermodynamic Integration and Free energy perturbation schemes for calculating the free energy differences. This on-the-fly calculation gives a lower variance estimate compared to the post-processing schemes that is generally used for the free energy calculations. We show the usage of the methods for a number of standard benchmark systems and give recommendations for its efficient usage. We expect that the ease of use and new functionalities in the CHARMM GPU code will help in wider adoption of alchemical free energy calculations in both pharmaceutical drug development and academic exploration.

On the fly alchemical free energy calculations on the GPU in CHARMM

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ACS Fall 2022

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