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

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

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.

• Jezik: Angleški jezik
• Ključne besede: chemical cross-linking, homo-oligomers, cross-link assignation ambiguity, solvent accessible surface distances, modeling
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2019
• Št. strani: 12 str.
• Številčenje: Vol. 20, art. 464
• PID: 20.500.12556/RUL-125376
• UDK: 577.112
• ISSN pri članku: 1471-2105
• DOI: 10.1186/s12859-019-3032-x
• COBISS.SI-ID: 1538315971
• Datum objave v RUL: 12.03.2021

Gradivo je del revije

• Naslov: BMC bioinformatics
• Založnik: Springer Nature
• ISSN: 1471-2105
• COBISS.SI-ID: 2433556

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 12.03.2021

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: prečno povezovanje, homo-oligomeri, nedoločljivost prečnih povezav, topilu dostopne razdalje, modeliranje

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: J1-7119
• Naslov: Biologija EpCAM na strukturnem nivoju kot osnova za učinkovito tumorsko ciljanje