Predicting ion mobility collision cross sections and assessing prediction variation by combining conventional and data driven modeling

The use of collision cross section (CCS) values derived from ion mobility studies is proving to be an increasingly important tool in the characterization and identification of molecules detected in complex mixtures. Here, a novel machine learning (ML) based method for predicting CCS integrating both molecular modeling (MM) and ML methodologies has been devised and shown to be able to accurately predict CCS values for singly charged small molecular weight molecules from a broad range of chemical classes. The model performed favorably compared to existing models, improving compound identifications for isobaric analytes in terms of ranking and assigning identification probability values to the annotation. Furthermore, charge localization was seen to be correlated with CCS prediction accuracy, with gas-phase proton affinity demonstrating the potential to provide a proxy for prediction error based on chemical structural properties. The presented approach and findings represent a further step towards accurate prediction and application of computationally generated CCS values.