The next generation of medicines will rely heavily upon our ability to quickly assess the structures and stabilities of complex macromolecular machines, determine the influence of large libraries of conformationally-selective small molecule binders on their stuctures, and conduct parallel higher-order structure (HOS) assessments of protein-based biotherapeutics.  Such endeavours are nearly insurmountable with current tools.  In this presentation, I will discuss recent developments surrounding the measurement and 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. This presentation will disclose our work to develop CIU into a validated analytical technology, including: new approaches for CIU signal processing, high-throughput CIU, and deploying CIU technology on the Agilent 6560 drift tube IM-MS platform. We will also dicuss recent work aimed at understanding the mechanism of protein CIU, as well as examples of the information content of such assays in the context of therapeutic antibodies and membrane proteins.

Collision induced unfolding: New tools for structural biology and drug discovery

2019 Spring National Meeting

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