Strategies for Selecting Computational Protocols in Support of Small Molecule Structural Analysis by Ion Mobility-Mass Spectrometry

Abstract

Structural ion mobility-mass spectrometry (IM-MS) is often paired with computational conformational space studies to provide more insight into the experimental measurements. From the IM-MS or gas phase electrophoresis experiment, drift times are measured for the gas phase ions, which are converted into collision cross section (CCS) values. This CCS value can be interpreted as a rotationally averaged surface area of the gas phase ion. By computationally modeling these molecular ions, actual three-dimensional structures can be assigned to these CCS values. Within this work a combination of IM-MS techniques with computational modeling have been used to study polymer precursors, natural products, and metabolites. With the addition of tandem MS, fragmentation pathways were suggested for polyurethane hard block precursors. A conformational sampling protocol based on distance geometry methods, which selects random, pairwise interatomic distances to generate three-dimensional conformations, was developed to generate conformations of gas phase ions in a more time efficient manner as compared to current molecular dynamics approaches. This method was benchmarked on set of natural product molecules and then used to generate theoretical CCS ranges for metabolites. Distance geometry generates all possible three-dimensional conformations for the molecular ion and therefore the theoretical ranges based on these conformations can serve as a guide for developing new databases of experimental metabolite CCS values. Selecting appropriate computational strategies provides important structural details that help interpret experimental IM-MS results.