Within each living organism proteins are at work, carrying out activities that impact every aspect of cellular function from synthesis to cell death. A key factor in varied protein functionality is their ability to self-assemble, creating vast molecular 'machines' capable of performing intricate, highly specialized tasks. To rapidly discover the structural properties of such assemblies, especially when bound to therapeutic small molecules, is a grand challenge for structural biology that is nearly insurmountable with current tools. In this presentation, I discuss recent developments surrounding ion mobility-mass spectrometry (IM-MS) methods to bridge this gap in basic technology. Our approach exploits a series of highly-accurate, gas-phase measurements of protein size and mass to rapidly determine multiprotein architectures and stabilities when bound to small molecules, without the need for covalent labels or tagging, and consuming 10-100 times less protein than almost any other label-free technology. Recent IM-MS applications, ranging from multi-protein topology construction to conformationally-selective drug discovery efforts, will be discussed.

Structural biology in the gas phase: New approaches for conformationally-selective inhibitor screening and multiprotein topology mapping

248th National Meeting (2014)

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