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The Importance of Non-accessible Crosslinks and Solvent Accessible Surface Distance in Modeling Proteins with Restraints From Crosslinking Mass Spectrometry

Bullock, JMA; Schwab, J; Thalassinos, K; Topf, M; (2016) The Importance of Non-accessible Crosslinks and Solvent Accessible Surface Distance in Modeling Proteins with Restraints From Crosslinking Mass Spectrometry. Molecular & Cellular Proteomics , 15 (7) pp. 2491-2500. 10.1074/mcp.M116.058560. Green open access

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Abstract

Crosslinking mass spectrometry (XL-MS) is becoming an increasingly popular technique for modeling protein monomers and complexes. The distance restraints garnered from these experiments can be used alone or as part of an integrative modeling approach, incorporating data from many sources. However, modeling practices are varied and the difference in their usefulness is not clear. Here, we develop a new scoring procedure for models based on crosslink data—Matched and Nonaccessible Crosslink score (MNXL). We compare its performance with that of other commonly-used scoring functions (Number of Violations and Sum of Violation Distances) on a benchmark of 14 protein domains, each with 300 corresponding models (at various levels of quality) and associated, previously published, experimental crosslinks (XLdb). The distances between crosslinked lysines are calculated either as Euclidean distances or Solvent Accessible Surface Distances (SASD) using a newly-developed method (Jwalk). MNXL takes into account whether a crosslink is nonaccessible, i.e. an experimentally observed crosslink has no corresponding SASD in a model due to buried lysines. This metric alone is shown to have a significant impact on modeling performance and is a concept that is not considered at present if only Euclidean distances are used. Additionally, a comparison between modeling with SASD or Euclidean distance shows that SASD is superior, even when factoring out the effect of the nonaccessible crosslinks. Our benchmarking also shows that MNXL outperforms the other tested scoring functions in terms of precision and correlation to Cα-RMSD from the crystal structure. We finally test the MNXL at different levels of crosslink recovery (i.e. the percentage of crosslinks experimentally observed out of all theoretical ones) and set a target recovery of ∼20% after which the performance plateaus.

Type: Article
Title: The Importance of Non-accessible Crosslinks and Solvent Accessible Surface Distance in Modeling Proteins with Restraints From Crosslinking Mass Spectrometry
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/mcp.M116.058560
Publisher version: http://dx.doi.org/10.1074/mcp.M116.058560
Language: English
Additional information: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Free via Open Access: OA Free via Creative Commons: CC-BY license.
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemical Research Methods, Biochemistry & Molecular Biology, Structural-characterization, Structure Prediction, Architecture, Microscopy, Chaperonin, Resolution, Tric/cct, Complex
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1494804
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