Characterize sensitivity to embedding parameters

Determine how the computed protein–ligand relative binding free energies depend on the atomic polarizabilities, effective dielectric constant, and Thole damping exponent used in the electrostatic-embedding MLIP/MM scheme.

Background

The electrostatic embedding implementation uses fixed atomic polarizabilities, an effective dielectric constant of ε = 2, and a Thole damping exponent of a = 1.3. These values are inherited or fixed rather than optimized for the present alchemical calculations. The influence of these choices on the resulting free energies is consequently unresolved.

References

We have not checked how sensitive the computed free energies are to any of these three.

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

What remains is functional form, whose two candidates we do not separate: torsions never fitted to an $N$-methylated peptide backbone, and the absent polarization response invoked for macrocycles of this class.

— UBio-MolFM: Enabling Biomolecular Dynamics at DFT Accuracy and $10^5$ Atoms with One Untuned Potential  (2608.18623 - Huang et al., 19 Aug 2026) in Section 1, subsection 3, paragraph beginning “What causes that flatness”; Methods, subsection “Classical-force-field baseline”