Mass spectrometry is a powerful analytical technique that can accurately measure the molecular masses of individual biomolecules, including peptides, proteins, and large intact protein assemblies. Chait’s lab specializes in the development of mass spectrometers and other tools and methods for investigating a variety of biological and biochemical phenomena.
Knowledge of the makeup, structure, and dynamics of protein assemblies is key to understanding many cellular processes. The Chait lab devises new tools, including those based on quantitative mass spectrometry, to identify and study the protein interactions within these assemblies. Another primary goal of the lab is to derive a functional definition of cellular protein assemblies.
The lab has recently developed potent approaches for elucidating proximal, distal, and transient protein–protein interactions in cellular milieus, and for determining distance restraints between amino-acid residues within large protein assemblies by chemical cross-linking and mass spectrometry. The long-term goal of this research is to develop a molecular microscope for defining cellular systems with scales spanning all the way from the dimensions of a cell to the atomic resolution of molecules.
The Chait lab also serves as the National Resource for the Mass Spectrometric Analysis of Biological Macromolecules, now in its 44th year of funding from the National Institutes of Health. Its major areas of activity are basic research in mass spectrometry and ion chemistry. Work is currently under way in Chait’s lab to develop novel tandem mass spectrometry (MS/MS) instrumentation for ultrasensitive, rapid, and comprehensive characterization of proteins. Most MS/MS is inherently extremely wasteful, since, at any given time, all ion species except for the one that is specifically isolated are thrown away. The Chait lab is investigating new strategies for overcoming this inefficiency using high-capacity traps to produce MS/MS information on all the trapped ion species without the usual scanning losses. The lab is also developing novel instrumentation for carrying out massively parallel mass spectrometry.
Another aim of the lab is to develop new methods to study viral–host protein interactions during the progression of highly dynamic viral infections. In particular, members of the Chait lab are developing techniques for simultaneously visualizing individual viral proteins in host cells and identifying their interacting macromolecular partners in space and time. Some of these techniques are already facilitating a greater understanding of both the molecular details of viral infections and the biology of the cell.
Most recently, the lab has developed new mass spectrometric techniques for defining repertoires of high-affinity antibodies that develop within humans and llamas against any given antigen, including endogenous human antibodies that are protective against HIV. They have also developed new methods for improving the sensitivity of electrospray ionization mass spectrometers.
Chait is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program, and the Tri-Institutional Ph.D. Program in Chemical Biology.