Why Do Structure Models Put a Drug Back Into a Filled Pocket?

Ian Quigley says current co-folding models still place a small molecule where a pocket used to be after that pocket has been filled in, removed, or broken.

Start with a protein the model has already seen, a pocket, and a chemical sitting in it. Change the amino acid sequence so the pocket is filled, as if with cement, or so the pocket is gone or much bigger. In the trials his group has run with current state-of-the-art models, the model shoves the molecule back into the old spot. He reads that as memory of the location, not as an understanding of the physics. A physical pocket depends on a small number of amino acids with hydrogen-bond positions sticking out, plus a bit of pi stacking. If those contacts are broken and the model understood the physics, it should refuse to put a molecule there.

Structural training sets are thin on those negatives. What gets crystallized is the protein that already holds the molecule. He says people are not making crystal structures of the disruptive mutants his lab makes for itself.