Improved Separation of Isomers in Trapped-Ion Mobility Spectrometry (TIMS) through Targeted Use of Ion Chemistry: Core Principles and Applications

• Applicant: Dr. Alexander Haack
• Subject Area: Analytical Chemistry ; Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561548276

The rapid and reliable separation of isomers is one of the major challenges in modern analytical chemistry, particularly for applications in biochemistry, biomedicine, pharmacology, and trace analysis. This is because isomeric molecules can behave drastically differently in biological systems despite their often similar physicochemical properties. There is a significant need, for example, to reliably distinguish and quantify isomeric metabolites in cells or isomeric impurities in drug synthesis. Due to the high requirements for selectivity and sensitivity, mass spectrometric (MS) methods are often used for this analysis today. Increasingly, ion mobility spectrometry coupled with MS (IM-MS) is being employed because it is a structure-sensitive separation technique, making it well-suited for separating isomers. To resolve ever finer structural differences between isomeric analytes, both high-resolution techniques, such as the Trapped Ion Mobility Spectrometry (TIMS) technique, and chemical modifications are used today. These modifications range from covalent derivatization of the analytes to complexation with metals and modification of the gas phase with dopants - all with the goal of further amplifying fine structural differences between (isomeric) analytes. In this project, detailed computer simulations will be combined with experimental work to establish the use of dopants in TIMS based on real separation problems. This combines the high-resolution capabilities of TIMS with a promising chemical modification already applied in other IM-MS techniques. Central to this work are the computer simulations based on the TAURUS pipeline developed by the applicant. Here, quantum chemical, collision trajectory, and reaction dynamics simulations are combined to predict the behavior of analytes within the TIMS under various dopant and instrument conditions. This allows resource-efficient in silico optimizations of the separation parameters and the simulations also enable correlation of measurements with molecular parameters, generating a deeper understanding of the underlying mechanisms. This understanding is crucial for applying the demonstrated results to further separation challenges in the future. The combination examined in this project of high-resolution IM-MS techniques with flexible chemical modification through dopant-addition, and the explanation of separation mechanisms at the molecular level will significantly enhance our ability to separate structurally similar isomers. Consequently, this project influences many areas in life sciences and trace analysis.

• DFG Programme: Research Grants