Hi Ed,
For instance, long time ago I, like many others before and after, have discovered that sometimes there are empty cavities inside proteins, which get filled with bulk solvent, resulting in negative density blobs. Not a big deal, really, but it was possible to appease the inner nitpicker by generating a mask in CNS, running it through USF's MAMA to remove isolated islands and supplying it to CNS refinement as an external mask. I haven't seen much change in R-factors (naturally), but the negative density was gone.
do you still have that model and data available so I can quickly reproduce these negative density blobs? I would be happy to do this tonight (instead of having Friday's evening beer). That would be a starting point for me to think how we can do it better. I have some data from other people but I would like to have some more cases in my hands before I start doing anything. Thanks! Pavel.