Proper evaluation of chemical cross-linking-based spatial restraints improves the precision of modeling homo-oligomeric protein complexes

Gaber, Aljaž (author), Gunčar, Gregor (author), Pavšič, Miha (author)

Background: The function of oligomeric proteins is inherently linked to their quaternary structure. In the absence of high-resolution data, low-resolution information in the form of spatial restraints can significantly contribute to the precision and accuracy of structural models obtained using computational approaches. To obtain such restraints, chemical cross-linking coupled with mass spectrometry (XL-MS) is commonly used. However, the use of XL-MS in the modeling of protein complexes comprised of identical subunits (homo-oligomers) is often hindered by the inherent ambiguity of intra- and inter-subunit connection assignment. Results: We present a comprehensive evaluation of (1) different methods for inter-residue distance calculations, and (2) different approaches for the scoring of spatial restraints. Our results show that using Solvent Accessible Surface distances (SASDs) instead of Euclidean distances (EUCs) greatly reduces the assignation ambiguity and delivers better modeling precision. Furthermore, ambiguous connections should be considered as inter-subunit only when the intra-subunit alternative exceeds the distance threshold. Modeling performance can also be improved if symmetry, characteristic for most homo-oligomers, is explicitly defined in the scoring function. Conclusions: Our findings provide guidelines for proper evaluation of chemical cross-linking-based spatial restraints in modeling homo-oligomeric protein complexes, which could facilitate structural characterization of this important group of proteins.

• Language: English
• Keywords: chemical cross-linking, homo-oligomers, cross-link assignation ambiguity, solvent accessible surface distances, modeling
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2019
• Number of pages: 12 str.
• Numbering: Vol. 20, art. 464
• PID: 20.500.12556/RUL-125376
• UDC: 577.112
• ISSN on article: 1471-2105
• DOI: 10.1186/s12859-019-3032-x
• COBISS.SI-ID: 1538315971
• Publication date in RUL: 12.03.2021

Record is a part of a journal

• Title: BMC bioinformatics
• Publisher: Springer Nature
• ISSN: 1471-2105
• COBISS.SI-ID: 2433556

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 12.03.2021

Secondary language

• Language: Slovenian
• Keywords: prečno povezovanje, homo-oligomeri, nedoločljivost prečnih povezav, topilu dostopne razdalje, modeliranje

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: J1-7119
• Name: Biologija EpCAM na strukturnem nivoju kot osnova za učinkovito tumorsko ciljanje