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Abstract:

Within each living organism proteins are at work, carrying out activities which impact every aspect of cellular function from synthesis to cell death. The next generation of medicines will rely heavily upon our ability to quickly assess the structures and stabilities of such complex macromolecular machines, as well as the influence of large libraries of conformationally-selective small molecule binders and protein-based biotherapeutics. Such endeavours are nearly insurmountable with current tools. In this presentation, I will discuss recent developments surrounding the activation of gas-phase protein complex ions aimed at bridging this gap in basic technology. One such development is collision induced unfolding (CIU), which uses ion mobility-mass spectrometry (IM-MS) to measure the stability and unfolding pathways of gas-phase proteins, without the need for covalent labels or tagging, and consuming 10-100 times less sample than almost any other label-free technology. In parallel with this approach, my lab are pursuing chemical modification strategies aimed at the improved liberation of sequence informative peptide fragments from intact protein complex precursor ions during collision induced dissociation (CID), enabling the assessment of protein quaternary structure and sequence simultaneously. Recent developments in understanding the mechanisms of protein CIU and CID, the ability of these tools to differentiate therapeutic antibodies and enable the discovery of conformationally-selective inhibitors, will be discussed.

Bio:

Brandon T. Ruotolo currently holds the rank of Professor with Tenure in the Department of Chemistry, University of Michigan. He earned his B.S. in Chemistry from Saint Louis University in 1999. Brandon then received his Ph.D. from Texas A&M University in 2004 under the direction of David H. Russell. He did his post-doctoral work at the University of Cambridge with Dame Carol V. Robinson, and was awarded the first ever Waters Research Fellowship in 2008. Brandon moved to the University of Michigan in 2009, where he began his independent career.

The Ruotolo research group at the University of Michigan seeks to enable breakthroughs in structural biology and drug discovery by leveraging the potential of ion mobility-mass spectrometry (IM-MS) for the comprehensive, 3D structural analysis of the proteome. To this end, Ruotolo and his team have studied the role of solvation on biomolecular structure, introduced collision induced unfolding (CIU) - a new fingerprinting technology capable of detecting the structural state of protein-ligand complexes and biotherapeutics, developed software packages for the enhanced interpretation and throughput of IM-MS and CIU data, and investigated the structural consequences of small molecule drug-like compounds upon binding amyloid peptides. Ruotolo鈥檚 work has resulted in over 115 peer-reviewed publications, and many awards, including the American Society for Mass Spectrometry Research Award, a National Science Foundation CAREER award, the Eli Lilly Young Investigator Award in Analytical Chemistry, the Protein Society Young Investigator Award, and the Agilent Thought Leader Award.