With support from the Chemical Measurement & Imaging (CMI) Program in the Division of Chemistry and partial co-funding from the Division of Molecular and Cellular Biosciences, Professor Bush and his group at the University of Washington are developing new methods to characterize the structures of biological molecules. State-of-the-art techniques being developed in the Bush lab enable new approaches to these measurements, addressing unmet needs for rapid characterization of the structures, assembly, heterogeneity, quality, and similarity of biological molecules. New theoretical and statistical methods are also being developed and applied to gain insight into the relationship between the gas-phase measurements and the solution-phase structures of the proteins studied. This knowledge will help answer important questions about the structure and function of proteins and protein complexes, which is important for understanding the molecular basis of life and disease. Students working in the Bush lab are trained in measurement science, data science, and communication, preparing them for success in a wide variety of careers, thereby increasing the economic competitiveness of the United States in the fields of analytical instrumentation and biotechnology. The group is also developing teaching modules to enable exposure of a wide range of students to the concepts underlying their research.
Although ion mobility (IM) mass spectrometry (MS) has many attributes that make it well positioned to fulfill unmet needs in structural biology and biophysics, concerns about the fidelity of solution- and gas-phase structures have inhibited the broader adoption of IM-MS technologies and reduced the confidence in structural models based on IM-MS. The Bush group is working to (1) characterize the effects of charge state on the structures of protein ions; (2) characterize the dynamics of protein ions rearrangements; and (3) increase the information content of current IM experiments and calculations using modern statistical methods. The outcomes of this research will address urgent needs in the IM-MS community by providing detailed knowledge of the structures and dynamics of native-like ions, developing more accurate methods for translating observables from IM-MS experiments into restraints for structural modeling, and developing a general method for translating structural models into accurate predictions of observables. This in turn will enable IM-MS to play a greater role in hybrid structural biology projects and initiatives. Virtual labs will be developed to enable exposure of students to IM-MS techniques even where IM-MS instrumentation is not available.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
