Detergent Screening With Hybrid Detergents Increases Observable Number of Protein Identities in Bottom‐Up Proteomics

Detergents are key reagents in bottom-up proteomics that create an apparent, yet underappreciated bias on observable proteomes. Maximizing the chemical diversity of detergents in parallelized screens is supposed to maximize observable proteomes if proteomics data sets of different detergents are combined. The aim of our work is to investigate the potential of fusing ionic and nonionic detergent headgroups into hybrid detergents for increasing the observable number of unique protein identities. Our data indicate that the solubilizing properties of hybrid detergents do not reflect an average of canonical detergents. The number of unique protein identities obtainable from an Escherichia coli screen increases from 1604 to 2169 when proteomics data sets from sodium dodecyl sulfate, dodecyltrimethylammonium bromide, dendritic triglycerol detergent, and related hybrid detergents are combined. Our data highlight the utility of cationic detergents and related hybrid detergents for enhancing observable proteomes. Detergent screening-based proteome reconstructions with canonical detergents and hybrid detergents present an interesting research direction towards improved proteome profiling applications.