Determine whether MBIS charges improve alchemical free-energy predictions

Determine whether an MBIS-trained variant of the electrostatic-embedding MLIP/MM scheme, using machine-learned MBIS partial charges instead of RESP charges, yields more accurate protein–ligand alchemical relative binding free energies.

Background

The study uses RESP charges because they are compatible with AMBER-family fixed-charge force fields and the AM1-BCC baseline. However, prior work cited by the paper found that MBIS charges agreed more closely with reference QM/MM embedding energies. The authors therefore leave unresolved whether the charge definition that is more accurate for embedding energies also improves production alchemical free-energy calculations.

References

We have not tested whether an MBIS-trained variant would perform better in the alchemical setting; the RESP choice is a compatibility argument, not an accuracy one.

— Evaluating Electrostatic Embedding MLIP/MM for Relative Binding Free Energy Calculations  (2608.13355 - Farr et al., 13 Aug 2026) in Section 3, subsection “Limitations”