Associate Chair for Research; Professor of Chemistry
About
Proteins act as the molecular machinery of cellular biology, executing numerous critical functions in the life cycle of every known organism. To perform their biological function, individual proteins associate, often in a transient manner, to form complexes. In some cases, proteins form vast interaction networks capable of performing intricate cellular tasks. Understanding the function of such protein assemblies is an important scientific goal for disciplines ranging from molecular medicine to physical chemistry. However, one of the chief bottle-necks in such scientific endeavors is the available technology for determining the structure and architecture of large protein complexes. While high-detail structural information can be obtained by X-ray diffraction analysis, this experiment requires the availability of a sufficient quantity of homogenous material and definition of suitable crystallization parameters. Both conditions are often difficult to meet and the number of atomic structures for multi-subunit complexes deposited in structural databases remains relatively low. Alternative methodologies such as electron microscopy (EM) and small angle X-ray scattering (SAXS) allow the determination of the surface envelope of complexes of sufficient dimensions, but interpretation of these data is aided by detailed knowledge of complex composition and is limited to homogeneous complexes. Consequently, there is a need to develop new approaches capable of defining the subunit stoichiometry, composition, and shape of heterogeneous macromolecular complexes of biological importance.
Our group is primarily focused on developing ion mobility-mass spectrometry (IM-MS), an emerging technology that can determine the composition, size, and topological organization of protein assemblies from a small amount of sample, in the presence of impurities and structural heterogeneity, as a tool for structural biology. This focus necessitates research projects that span a wide range of topics. Some of these projects are focused on classical analytical chemistry, including IM-MS instrument development and the construction of computational tools for IM-MS data analysis and 3D model generation. Other projects focus on the collision induced unfolding (CIU) of protein complexes in the gas-phase, which we are building into a technology for protein inhibitor discovery and rapid biotherapeutic characterization. Still others involve the study of protein self-assembly, aggregation and amyloid formation. Our long-term aim is utilize IM-MS data alongside other protein structure determination approaches to support the emerging field of integrative structural biology – where many pieces of data derived from disparate techniques are combined to generate a more-complete picture of an assembly than was possible with any one tool.
Awards
Biemann Medal from the American Society for Mass Spectrometry, 2023
NSF Two-Year Extension for Special Creativity, 2020
Agilent Thought Leader Award, 2018
Protein Society Young Investigator Award, 2018
Eli Lilly Young Investigator Award, 2013
National Science Foundation CAREER Award, 2013
American Society for Mass Spectrometry Research Award, 2011
Ralph E. Powe Junior Faculty Enhancement Award, 2011
Waters Research Fellowship, University of Cambridge, 2009
Tomas A. Hirschfeld Award for Outstanding Graduate Research, 2003
Leopold Marcus Award for Undergraduate Research Excellence, 1999
I.M. Kolthoff Enrichment Award, 1998
Selected Recent Review Articles
"Collision induced unfolding of isolated proteins in the gas phase: past, present, and future" SM Dixit, DA Polasky, BT Ruotolo (2018) Curr. Opin. Chem. Biol. 42, 93-100
"The growing role of structural mass spectrometry in the discovery and development of therapeutic antibodies" Y Tian, BT Ruotolo (2018) Analyst 143 (11), 2459-2468
"Coming to grips with ambiguity: ion mobility-mass spectrometry for protein quaternary structure assignment" JD Eschweiler, AT Frank, BT Ruotolo (2017) J. Am. Soc. Mass Spectrom. 28 (10), 1991-2000
"Sizing Up Protein–Ligand Complexes: The Rise of Structural Mass Spectrometry Approaches in the Pharmaceutical Sciences" JD Eschweiler, R Kerr, J Rabuck-Gibbons, BT Ruotolo (2017) Annual Review of Analytical Chemistry 10, 25-44
Research Areas(s)
- Analytical Chemistry
- Bioanalytical Chemistry
- Biophysical Chemistry
- Chemical Biology
