I have been fascinated with the subject of the “dark proteome” since I entered the field of mass spectrometry-based proteomics in 2001. What are all those mass spectra that we cannot identify in a typical proteomics experiment, and how do we design efficient computational strategies to move beyond standard analyses? To this end, we have created a highly efficient peptide indexing algorithm and implemented it in an ultrafast peptide identification tool, MSFragger, which has become the engine behind our widely used FragPipe computational platform. Our algorithms have empowered new strategies for faster and more sensitive identification of biologically or chemically modified peptides and proteins. We will describe recent computational advances and applications of our algorithms in the areas of immunopeptidomics and chemical proteomics. We will also discuss our efforts to enable proteogenomics searches for novel peptides arising from alternative splicing, mutations, or non-canonical translations, including our PepCentric computational resource for rapid proteogenomics searches across repository-wide mass spectrometry datasets.

Alexey Nesvizhskii is the Godfrey Dorr Stobbe Professor of Bioinformatics in the Departments of Pathology and Computational Medicine & Bioinformatics at the University of Michigan, Ann Arbor. He also directs the Proteomics Resource Facility, which offers cutting-edge proteomics capabilities to investigators at the University of Michigan. He earned his PhD in Physics from the University of Washington in Seattle in 2001, followed by postdoctoral research in proteomics with Prof. Ruedi Aebersold at the Institute for Systems Biology. He has been on the faculty at the University of Michigan since 2005. His research focuses on mass spectrometry-based proteomics and proteogenomics, bioinformatics, and multi-omics data integration. The computational algorithms and software tools developed by Dr. Nesvizhskii and his group are utilized by thousands of laboratories worldwide. Additionally, he has developed and taught numerous internationally recognized hands-on workshops and tutorials on mass spectrometry-based proteomics data analysis. He has published over 250 manuscripts in international scientific journals. Alexey has received several prestigious awards, including the Distinguished Achievement in Proteomic Sciences Award from the Human Proteome Organization and the Gilbert S. Omenn Computational Proteomics Award.