Chemical cross-linking coupled to mass spectrometry was used to investigate the conformations of the apolipoprotein isoforms apoE2, apoE3, and apoE4. Cross-linking data was generated using the reagents disuccinimidyl suberate (DSS), pimelic dihydrazide (PDH), and 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium (DMTMM) chloride. Intramolecular interactions derived from the cross-linking experiments were combined with molecular modeling approaches.