When you do "File > Import > Results" in Skyline, there is a dropdown at the bottom of the "Import Results" dialog which asks you how many files to import simultaneously.
You will probably have better performance if you choose "One at a time".
If Skyline ever tries to use more RAM than you have in your computer, things really will become about a million times slower. The reason for this has to do with the way that garbage collection in Microsoft .Net behaves when it is using the memory swap file. If you tell Skyline to extract chromatograms from too many files at once, then Skyline will probably be able to avoid using more memory than is in the computer.
We generally recommend that you extract chromatograms from .mzML files instead of .mzXML, although that probably would not have an impact on the amount of memory that Skyline is consuming. Skyline can also extract chromatograms from the original raw files, which often works better than mzML.
If you send us your Skyline document and one or more of your raw files we can give you more advice about what you can do to speed things up.
In Skyline you can use the menu item:
File > Share
to create a .zip file containing your Skyline document and supporting files including extracted chromatograms and spectral libraries.
Files which are less than 50MB can be attached to this support request. You can upload larger files here:
I cannot tell from your screenshot how many peptides are in your document. If you added all of the theoretical tryptic peptides from the human protein fasta file, that might be too many to reasonably handle at once. You can reduce the number of peptides in your document by changing the settings on the "Filter" and "Library" tabs at "Settings > Peptide Settings".
You also might be able to make your Skyline document smaller by changing the settings on the "Filter" and "Library" tabs at "Settings > Transition Settings".
By the way, we have made some memory improvements in Skyline-Daily. You might find things work faster if you try this in Skyline-Daily instead of Skyline 21.1.
We will release the new version of Skyline (21.2) in a few weeks which will have these memory performance improvements that are currently only available in Skyline-Daily.
We have a page which some helpful tips about how to extract chromatograms faster when using Skyline from the commandline: