Dear Careina,
First: make sure your solution is completely free of competing primary amines,
e.g. tris buffer. Phosphate buffers or HEPES should be used; if you need buffer
exchange, do it by gel filtration or extensive dialysis (2-3 changes), not
concentration-dilution.
Second: Try to use BS3, which is a water-soluble analogue of DSS; this gives
generally excellent results for non-membrane proteins.
Third: test a few other crosslinkers. Dimethyl pimelimidate and dimethyl
Suberimidate are amine-directed crosslinkers with different lengths which have
worked in some cases. A very dirty crosslinker is glutaraldehye which, with
time, will crosslink everything into large aggregates, but you may be able to
fiddle with the conditions (low concentrations of glutaraldehyde and protein).
