Electron capture/transfer versus collisionally activated/induced dissociations: solo or duet?

New ion fragmentation technologies--electron capture dissociation (ECD) and electron-transfer dissociation (ETD)--are based on interaction of multiply charged polypeptides with either free electrons (ECD) or anionic species (ETD). After initial difficulties, these ECD/ETD (ExD) technologies are now being increasingly implemented in high-throughput proteomics work. This critical analysis presents arguments for the combined use of ExD with the conventional low-energy collisional excitation CID/CAD (CxD). It is argued that the database search, a key technology in MS/MS-based proteomics, is vulnerable with respect to the incomplete sequence information obtainable with either of the techniques, peptide MS/MS homology being a major complicating factor. De novo sequencing is viewed as the only adequate answer to this challenge and it can be achieved only with combined use of ExD and CxD. The payoff in the form of additional sequence information is projected to exceed the costs of such implementation. The greatest impact of combining ExD and CxD is expected in high-resolution instruments.