SIM-XL performs a fully specific search for cross-linking identification, because it has been designed to work on searches with non-cleavable cross-linkers. In this case, it requires small databases.
However, when a large database is used, there is a feature responsible for reducing it where SIM-XL uses a strategy to figure out peptides that contain dead-end modification (hydrolyzed bond peptides) in order to create a new database that contains only the proteins inferred by the identified dead-end modified peptides.
This strategy works for both fully-specific and semi-specific searches. And you can use this feature even if you have a small database (We don't recommend it once you will increase the search space, in consequence, will increase the number of false-positives).
To do so, go to XL Advanced Parameters and Enable the option "Dynamic DB Reduction". You can use the fields XCorr Threshold and Min # Peptides as 2.5 and 2, respectively. Afterwards, go back to the main tab (XL Search) and change the "Enzyme Specificity" field to "Semi-specific".
Yes, we could.
In this case, SIM-XL will work as the traditional search, i.e., taking into account the protein without labeling.
If you have any further questions, just email us.