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bioRxiv · 10.1101/2023.01.20.524983

High sensitivity proteome-scale search for crosslinked peptides using CRIMP 2.0

Crowder, D. A.·Sarpe, V.·Amaral, B. C.·Brodie, N. I.·Michael, A. R. M.·Schriemer, D. C. C.
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Abstract

Crosslinking mass spectrometry (XL-MS) is a valuable technique for the generation of point-to-point distance measurements in protein space. Applications involving in situ chemical crosslinking have created the possibility of mapping whole protein interactomes with high spatial resolution. However, an XL-MS experiment carried out directly on cells requires highly efficient software that can detect crosslinked peptides with sensitivity and controlled error rates. Many algorithmic approaches invoke a filtering strategy designed to reduce the size of the database prior to mounting a search for crosslinks, but concern has been expressed over the possibility of reduced sensitivity with such strategies. Here we present a full upgrade to CRIMP, the crosslinking app in the Mass Spec Studio, which implements a new strategy for the detection of both component peptides in the MS2 spectrum. Using several published datasets, we demonstrate that this pre-searching method is sensitive and fast, permitting whole proteome searches on a conventional desktop computer for both cleavable and noncleavable crosslinkers. We introduce a new strategy for scoring crosslinks, adapted from computer vision algorithms, that properly resolves conflicting XL hits from other crosslinking reaction products, and we present a method for enhancing the detection of protein-protein interactions that relies upon compositional data.

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Crowder, D. A., Sarpe, V., Amaral, B. C., Brodie, N. I., Michael, A. R. M., Schriemer, D. C. C.. 2023-01-21. High sensitivity proteome-scale search for crosslinked peptides using CRIMP 2.0. https://doi.org/10.1101/2023.01.20.524983

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