Extracting Atomic Contributions to Binding Free Energy Using Molecular Dynamics Simulations with Mixed Solvents (MDmix)

Background: Mixed solvents MD (MDmix) simulations have proved to be a useful and increasingly accepted technique with several applications in structure-based drug discovery. One of the assumptions behind the methodology is the transferability of free energy values from the simulated cosolvent molecules to larger drug-like molecules. However, the binding free energy maps (ΔGbind) calculated for the different moieties of the cosolvent molecules (e.g. a hydroxyl map for the ethanol) are largely influenced by the rest of the solvent molecule and do not reflect the intrinsic affinity of the moiety in question. As such, they are hardly transferable to different molecules.

Method: To achieve transferable energies, we present here a method for decomposing the molecular binding free energy into accurate atomic contributions.

Result: We demonstrate with two qualitative visual examples how the corrected energy maps better match known binding hotspots and how they can reveal hidden hotspots with actual drug design potential.

Conclusion: Atomic decomposition of binding free energies derived from MDmix simulations provides transferable and quantitative binding free energy maps.