The challenge of the proteome dynamic range and its implications for in-depth proteomics

The dynamic range of the cellular proteome approaches seven orders of magnitude-from one copy per cell to ten million copies per cell. Since a proteome's abundance distribution represents a nearly symmetric bell-shape curve on the logarithmic copy number scale, detection of half of the expressed cellular proteome, i.e. approximately 5000 proteins, should be a relatively straightforward task with modern mass spectrometric instrumentation that exhibits four orders of magnitude of the dynamic range, while deeper proteome analysis should be progressively more difficult. Indeed, metaanalysis of 15 recent papers that claim detection of >5000 protein groups reveals that the half-proteome analyses currently requires ≈5 h of chromatographic separation, while deeper analyses yield on average ≤20 new proteins per hour of chromatographic gradient. Therefore, a typical proteomics experiment consists of a "high-content" part, with the detection rate of approximately 1000 proteins/h, and a "low-content" tail with much lower rate of discovery and respectively, lower cost efficiency. This result calls for disruptive innovation in deep proteomics analysis.