Sheenam paper on self-RBFEs and ATM with Metadynamics sampling

A recent preprint on ArXiv describes the recent work by Sheenam about addressing the relatively large statistical fluctuations that often affect alchemical relative binding free energies of protein-ligand binding calculations. The salient results:

• Self Relative Binding Free Energy (self-RBFE) calculations between a ligand and an identical copy of the same ligand are useful tools to probe the statistical errors that come with RBFE estimates.

• We found that the statistical errors likely contribute a major fraction of the errors observed in RBFE validation studies. To improve the models we need to reduce the statistical uncertainties of the predictions.

• Many ligands are affected by severe conformational reorganization in going from the solution conformations to the bound conformations. For these ligands, metadynamics conformational sampling on some of the degrees of freedom of the ligand goes a long way toward reducing the statistical variance of self-RBFE estimates. Advanced conformational sampling of the ligand degrees of freedom is predicted to improve the accuracy of the predictions on actual RBFE estimates.