Quantum Chemistry Calculation-Assisted Large-Scale Collision Cross Section Prediction Empowers...

Derivatization-enhanced multidimensional metabolomics combined with ion mobility mass spectrometry will greatly improve the accuracy and coverage of metabolic analysis. However, accurate prediction of the large-scale collision cross section (CCS) of derivatized metabolites without relying on standards and the establishment of multidimensional analytical methods faces great challenges. Here, we propose quantum chemistry calculation-assisted machine learning strategies applicable to the accurate prediction of the CCS of derivatized sterols, develop C═C bond-targeted N-Me derivatization methods for unsaturated sterols, and create a large-scale, 4D information database of derivatized sterol lipids (n = 4891) by combining retention time and fragment ion prediction. Furthermore, a high-coverage unsaturated sterolomics at the isomer level was established on this basis, which quantitatively revealed the tissue-specific distribution patterns of over 100 sterol lipids. This study provides a key foundation for derivatization-enhanced metabolomics and provides important techniques and information for metabolic and functional studies of sterols.