Without knowing the technical answer: what kind of resolution would you need to answer your scientific question? Will the outer density (which is the answer that cryoEM ultimately provides) answer this question? Do you trust that your protein is pure and uniform enough in modification state and geometry that you will receive a good answer? Do you have additional information you can integrate (Xray of protein substructures etc)? In many cases, no single technique will provide a complete answer. You will probably have to combine cryoEM with e.g. crosslinking-MS intensive modeling/docking to acheive an answer.

There is a short summary about "How big is the “average” protein?" available with also some nice figures that are courtesy of David Goodsell under http://book.bionumbers.org/how-big-is-the-average-protein/ . Based on this it seems to be worth to characterize a protein with 2000 amino acid residues. We use only cryo-SEM on a JEOL 7200 and have therefore no own experience with TEM, but we expect that work will be challenging and has to include other methodologies, also...

It would be nice to hear from your experiences!

Hi Sarah Bartlett , Given the configuration and setup you told, it might be challenging. LaB6 filament is not a good idea for getting high resolution since the energy spread and coherence is an issue. This will affect contrast transfer function and hence the resolution attained. Direct electron detectors have much higher DQE, which takes into account the efficiency of each electron.