PT  - JOURNAL ARTICLE
AU  - Kumar Yugandhar
AU  - Ting-Yi Wang
AU  - Shayne D. Wierbowski
AU  - Elnur Elyar Shayhidin
AU  - Haiyuan Yu
TI  - Structure-based validation can drastically under-estimate error rate in proteome-wide cross-linking mass spectrometry studies
AID  - 10.1101/617654
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 617654
4099  - http://biorxiv.org/content/early/2019/12/25/617654.short
4100  - http://biorxiv.org/content/early/2019/12/25/617654.full
AB  - Recent, rapid advances in cross-linking mass spectrometry (XL-MS) has enabled detection of novel protein-protein interactions and their structural dynamics at the proteome scale. Given the importance and scale of the novel interactions identified in these proteome-wide XL-MS studies, thorough quality assessment is critical. Almost all current XL-MS studies validate cross-links against known 3D structures of representative protein complexes. However, current structure validation approach only includes cross-links where both peptides mapped to the 3D structures. Here we provide theoretical and experimental evidence demonstrating this approach can drastically underestimate error rates for proteome-wide XL-MS datasets. Addressing current shortcomings, we propose and demonstrate a comprehensive set of four metrics, including orthogonal experimental validation to thoroughly assess quality of proteome-wide XL-MS datasets.