A Selective History of Protein Sequencing and the Impact of Donald F. Hunt on Protein Sequencing by Tandem Mass Spectrometry.

This review is a selective history of protein sequencing through the year 2000, intended to illuminate just how challenging it was to establish the methods that enabled protein analysis, especially protein analysis by mass spectrometry. My goal is to provide context to the development and impact of mass spectrometry-based methods on protein sequencing over the last 75 years and to highlight the significant research critical to the development of protein sequencing methods. Because the chemistry of proteins is so diverse, an easy "one size fits all" protein sequencing method (such as the methods available for sequencing DNA) was not feasible. The original protein sequencing methods pursued by Sanger, Du Vigneaud, and Edman relied on chemical methods to decipher amino acid sequences, but in 1959 Klaus Biemann used mass spectrometry to analyze di- and tripeptides, thus introducing the use of mass spectrometry to the protein sequencing field. Donald F. Hunt of the University of Virginia was the first to develop tandem mass spectrometry-based methods for sequencing peptides and proteins, and many of his methods are in use to this day. Hunt made landmark contributions in mass spectrometry technology development and applied his tandem mass spectrometry methods widely across biology, particularly in the field of immunology. The aim of this review is to provide a historical context for Hunt's contributions (as well as other mass spectrometrists!) to protein sequencing and proteomics and to honor Dr. Hunt's contributions upon his retirement.