A New Structural Model of Apolipoprotein B100 Based on Computational Modeling and Cross Linking

Kianoush Jeiran, Scott M. Gordon, Denis O. Sviridov, Angel M. Aponte, Amanda Haymond, Grzegorz Piszczek, Diego Lucero, Edward B. Neufeld, Iosif I. Vaisman, Lance Liotta, Ancha Baranova, Alan T. Remaley

Research output: Contribution to journalArticlepeer-review


ApoB-100 is a member of a large lipid transfer protein superfamily and is one of the main apolipoproteins found on low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particles. Despite its clinical significance for the development of cardiovascular disease, there is limited information on apoB-100 structure. We have developed a novel method based on the “divide and conquer” algorithm, using PSIPRED software, by dividing apoB-100 into five subunits and 11 domains. Models of each domain were prepared using I-TASSER, DEMO, RoseTTAFold, Phyre2, and MODELLER. Subsequently, we used disuccinimidyl sulfoxide (DSSO), a new mass spectrometry cleavable cross-linker, and the known position of disulfide bonds to experimentally validate each model. We obtained 65 unique DSSO cross-links, of which 87.5% were within a 26 Å threshold in the final model. We also evaluated the positions of cysteine residues involved in the eight known disulfide bonds in apoB-100, and each pair was measured within the expected 5.6 Å constraint. Finally, multiple domains were combined by applying constraints based on detected long-range DSSO cross-links to generate five subunits, which were subsequently merged to achieve an uninterrupted architecture for apoB-100 around a lipoprotein particle. Moreover, the dynamics of apoB-100 during particle size transitions was examined by comparing VLDL and LDL computational models and using experimental cross-linking data. In addition, the proposed model of receptor ligand binding of apoB-100 provides new insights into some of its functions.

Original languageEnglish
Article number11480
JournalInternational Journal of Molecular Sciences
Issue number19
StatePublished - Oct 2022

Bibliographical note

Funding Information:
Research was supported by intramural DIR funds from the National Heart, Lung and Blood institute (HL006095-13).

Publisher Copyright:
© 2022 by the authors.


  • apolipoprotein B100
  • cardiovascular disease
  • divide and conquer algorithm
  • DSSO cross-linker
  • homology modeling
  • LDL receptor ligand
  • lipovitellin
  • very low-density lipoprotein

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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