Liquid chromatography coupled online to nano-electrospray ionization (nESI) tandem mass spectrometry is the analytical workhorse in the field of proteome research. Dimethyl sulfoxide (DMSO) was recently shown to improve nESI efficiency by a factor of three to ten thus improving the sensitivity and coverage of proteomic experiments. However, relatively few investigations into which solvent additives promote nESI response have been performed at a proteomic scale. Here, we systematically evaluated the concept by screening about 30 compounds with various physico-chemical properties. Detailed further analysis showed that ethylene glycol performed similarly to DMSO and the results indicate that enhancing the nESI response of peptides by simple solvent additives is a valid and promising approach. Ethylene glycol may serve as a viable alternative to DMSO in applications where DMSO has disadvantages. In keeping with nESI theory, the key properties of an effective solvent additive for proteomic applications are a boiling point higher than water, low surface tension, and preferably high polarity for reversed phase LC-MS/MS applications.

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