A general, efficient and robust method to calculate free energy difference between systems

TL;DR

This paper introduces a new, efficient, and robust method for calculating free energy differences between systems, overcoming phase space overlap issues and enhancing automation in computational chemistry applications.

Contribution

The proposed method transforms each system into a replica with relaxed energy terms, simplifying the calculation and improving robustness compared to existing approaches.

Findings

Demonstrates high efficiency and robustness across various comparisons

Reduces the need for large phase space overlap

Outperforms traditional methods in automation and accuracy

Abstract

Calculating free energy differences is a topic of substantial interest and has many applications including molecular docking and hydration, solvation, and binding free energies which is used in computational drug discovery. However, in equilibrium methods the compared molecules are required to have large phase space overlap, which is usually not satisfied for two random systems, and there remain the challenges of robustness and automation. Here a highly efficient and robust method, that enables a wide range of comparisons, will be introduced, demonstrated and compared. In this method instead of transforming between one system into the other to perform the calculation each system is transformed into its replica with the different long range energy terms relaxed, which is inherently correlated with the original one, in order to eliminate the partition function difference arising from these terms. Then, since each transformed system can be treated as non interacting systems, the remaining difference in the (originally highly complex) partition function will cancel out.