Ion mobility spectrometry (IMS), and particularly differential IMS or FAIMS, is emerging as a versatile tool for separation and identification of gas-phase ions, especially in conjunction with mass spectrometry. For over two decades since its inception, the utility of FAIMS was constrained by resolving power (R) of less than ~20. Stronger electric fields and optimized gas mixtures have recently raised achievable R to ~200, but further progress with such approaches is impeded by electrical breakdown. However, the resolving power of planar FAIMS devices using any gas and field intensity scales as the square root of separation time (t). Here, we extended t from the previous maximum of 0.2 s up to fourfold by reducing the carrier gas flow and increased the resolving power by up to twofold as predicted, to >300 for multiply-charged peptides. The resulting resolution gain has enabled separation of previously “co-eluting” peptide isomers, including folding conformers and localization variants of modified peptides. More broadly, a peak capacity of ~200 has been reached in tryptic digest separations.
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