In Silico Reagent Design for Electron-Transfer Dissociation on a Q‑TOF

Electron-transfer dissociation is an important technique capable of probing the primary and higher order structure of a wide variety of biomolecules and yielding information that is often inaccessible using other common MS methods. The source of the electron used to initiate the fragmentation event is a radical anion, and the fragmentation process therefore depends intimately on the electronic properties of both the reagent and analyte ions. A good reagent must ionize easily and be sufficiently robust to survive transport to the reaction location, but must also be capable of donating an electron to analyte cations efficiently enough to overcome competition with other ion–ion reaction channels. Inspired by the work of Gunawardena et al. (J. Am. Chem. Soc. 2005, 127, 12627), an in silico workflow to allow prescreening of potential electron-transfer reagents for use in glow-discharge sources is described. Approximately 150 candidate molecules have been characterized using this workflow. We discuss in detail the properties of a selected subset of singly and doubly substituted benzenes and introduce five effective new reagents that have been identified as a result of this work.