The Next Generation of Protein Sequencing and Analysis Methods

Advances in protein sequencing and analysis are poised to transform proteomics through an ability to link sequence, structure, and function at scale, thereby accelerating biological discovery and biomedical innovation. However, interrogating proteins is uniquely challenging because they cannot be amplified, are composed of complex chemical structures, and exist across a vast landscape of proteoforms. Techniques such as mass spectrometry typically drive large-scale proteomics studies; however, a new generation of technologies is pushing the boundaries, promising new features such as de novo, single-molecule, and/or higher-throughput sequencing and analysis. While many strategies are still in an early stage, a few modalities, such as fluorosequencing, single-molecule sequencing, digital proteomics mapping, and nanopore-based protein sequencing, have now reached or are thought to be nearing commercial implementation. In this review, we evaluate the mechanisms, current progress, and remaining challenges of these technologies while also highlighting how recent innovations are converging toward a new generation of proteomic technologies.