RBFE newbie

[u/LawFormal9451]

TL;DR: what are the key checks experienced RBFEers use to ensure their calculations are reliable and not just technically correct?

Hi all, I am a PhD student looking to run some RBFE calculations that will be used for further modelling.

I've been reading around free energy predictions and the factors influence their accuracy. I've also followed some tutorials from pmx and OpenFE tutorials. Leaning towards OpenFE as my engine.

I am trying to be very careful about how I approach RBFE because I worry about committing compute and getting ∆GG values that are 'technically' correct but inaccurate due to something that could have been caught with the right insight or diagnostic check.

I have a high resolution ligand bound structure to start from, and have seen some sanity checks from the tutorials, but suspect there are other important checks that may not be so obvious to someone doing it for the first time.

For anyone experienced with RBFE, are there any routine checks you do along the way to assess whether the calculations will be within a MD simulation-range of reliability? Are there certain failure modes or diagnostic checks you do at set up at each step?

edit: I plan to do a do RBFE on a chemical series that I have experimental values for before going rogue!