[ccp4bb] Negative electron density in the Fo-Fc map at the binding site

[Armando Albert]

Dear all, 
I am screening a small library of ligands against my protein crystals.  
Following a soaking with different ligands, I collect datasets to 1.9A 
resolution and refine them against an empty model  without any problem.  
What is the meaning of a rather large negative electron density in the Fo-Fc 
map at the binding site?. Could it be related to an incorrect bulk solvent 
model?
Thank you in advance
Armando