There are multiple avenues you could explore.

If you think handling is an issue, you could look into growing and collecting 
with "in situ"  plates.

You could test for diffraction at room temp, or even get a full data set at 
room temp by combining data from multiple crystals. If diffraction is not good 
at room temp, it is probably not going to be better under cryo conditions.

As for cryo, instead of trying cryoprotectant A or cryoprotectant B, you could 
try a mixture of multiple cryoprotectants:

https://pubs.acs.org/doi/abs/10.1021/acs.cgd.5b01692
Use of Multiple Cryoprotectants to Improve Diffraction Quality from Protein 
Crystals
Senda, et al.
https://doi.org/10.1021/acs.cgd.5b01692

Evidence of Kinetic Cooperativity in Dimeric Ketopantoate Reductase from 
Staphylococcus aureus
JE Sanchez, PG Gross, RW Goetze, RM Walsh Jr, WB Peeples, ZA Wood
Biochemistry 54 (21), 3360-3369

=======================================================================
 All Things Serve the Beam
 =======================================================================
                                 David J. Schuller
                                 modern man in a post-modern world
                                 MacCHESS, Cornell University
                                 [email protected]
________________________________
From: CCP4 bulletin board <[email protected]> on behalf of Blake, Morgan 
Elizabeth <[email protected]>
Sent: Wednesday, November 22, 2023 11:44 AM
To: [email protected] <[email protected]>
Subject: [ccp4bb] Fragile Crystals

Hello!

I am a PhD student working on a crystallography project to wrap up my 
dissertation research. I have purified a complex of two proteins, and I can 
consistently grow crystals in 10% PEG3350, 0.2M KSCN, 0.1M BIS-TRIS propane pH 
7.5. These crystals have sharp edges and can grow to a large size (greater than 
0.5 mm), but the crystals seem to be very fragile. When we open the drops to 
harvest the crystals, we have little time to harvest the crystals before they 
crack. When we move the crystals to a cryoprotectant, over time they start 
fracturing. We've tried using different percentages of glycerol, ethylene 
glycol, PEG400, and oil for cryoprotectants with no success. Needless to say, 
the crystals do not diffract well, with spot patterns that look very 
streaky/mosaic, which I presume is due to the defects that we see in 
harvesting/handling. We have screened for alternate crystallization conditions, 
but we seem to get the same morphology in other conditions. Does anyone have 
suggestions for additives we could use post-crystallization to help stabilize 
our crystals?

Thanks for your advice!

________________________________

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