Can I compare binding affinity of different ligands using Rosetta?

Hi Athena,

It’s been a long time since I’ve docked ligands with Rosetta. I also did not attend the virtual workshop. But here are a few things to consider:

• The score function matters. Take a look at this recent manuscript put out by the Meiler lab. I’m not sure which strategy was presented at the virtual workshop but you might re-score your models with the RosettaLigand score function. In direct answer to your question, take a look at Figure 2B of the linked manuscript: RosettaLigand performs well in Spearman rank correlation tests.
• The pNear metric has been shown to correlate with binding energy. Have you calculated this metric for each ligand in your set?
• Have you performed any clustering to ensure the decoys chosen for the interface_delta score are well populated? If the conformation is only sparsely populated it may be unlikely to actually form. Try correlating the average-of-top-5 interface delta of the largest clusters to the wet-lab results.
• In protein:protein interface design the binding density is sometimes utilized to track best models. (Binding density is binding energy / buried surface area.) For small molecules the parameter is ligand efficieny, which is binding energy divided by the number of atoms.
• On occasion, a model with good binding energy can actually have a poor total score. It can sometimes be useful to cull the lowest 5-10% of models by total score before sorting by binding energy.

Hope that helps,

David