Temperature, Time, and Topology: New Frameworks for Advancing Ion Mobility - Mass Spectrometry

This research group at the University of Washington is developing next-generation tools for measuring the sizes, shapes, and stability of proteins and other molecules using ion mobility – mass spectrometry. The structures and dynamics of molecules govern how they function, and accurate measurements of molecular structure support advances ranging from the discovery of new medicines to the design of functional nanomaterials. Yet current methods are limited in their speed and accuracy, and results obtained on instruments in different laboratories can be difficult to compare. This project is creating fast computational methods for interpreting these measurements, together with a new experimental method that provides precise, independent control over the conditions used to probe molecules and addresses long-standing barriers to standardization. In biotechnology, these tools could accelerate the characterization of protein therapeutics, including antibody drugs, and the identification of small molecules that stabilize disease-related proteins, supporting the development of new medicines. The methods and software developed will be released as free, open-source resources for the research community. By making sophisticated measurements possible on low-cost computers and comparable across laboratories, these freely available tools will strengthen domestic capabilities in analytical instrumentation and biotechnology. The project will also strengthen the scientific workforce by training two graduate students and at least one undergraduate researcher in state-of-the-art chemical measurements and data science. The team will also expand and disseminate educational materials from a national mass spectrometry workshop, broadening access to training in the fundamentals of measurement technology. This project is advancing ion mobility – mass spectrometry through two complementary innovations. First, the project is developing MobileMesh, a computational framework that represents the surfaces of ions as triangle meshes and calculates collision cross sections by repurposing ray-casting algorithms from computer graphics, rather than approximating ions as collections of spheres. This approach will enable accurate calculations on standard desktop computers for systems ranging from small drug-like molecules to protein complexes, with surfaces derived from quantum mechanical calculations, atomic models, and cryo-electron microscopy densities. Second, the project is developing and validating Conformational Landscapes Observed through Controlled Kinetics (CLOCK), an experimental method providing independent control of the effective temperature of ions, from ambient to approximately 600 K, and the duration of their activation, from sub-milliseconds to seconds. Unlike conventional activation, in which elevated internal energies persist only fleetingly, CLOCK will enable detailed characterization of the free-energy landscapes that govern molecular structure and dynamics. Together, these computational and experimental advances will create a unified framework for relating measured quantities to molecular structure across a wide range of length and time scales. 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.