School of Chemistry Colloquium: Dr Yi Jin Metal Fluoride Complexes Reveal Changes of Dynamic and Modified Oncogene Proteins

Abstract: GTP hydrolysis is central to biology, being involved in regulating a wide range of cellular processes. In recent years, there has been more success in the potential therapeutic strategy to target KRas oncoprotein–driven cancers. However, multiple mechanistic possibilities of GTPases (Ras, Rho, Ran, Rab, etc) catalysed hydrolysis accelerated by GTPase activating protein (GAP) both with and without the “arginine finger”, have been proposed based on limited experimental evidence and computational data. This continued uncertainty hampers both our fundamental understanding of biological GTP hydrolysis and ongoing drug discovery efforts targeting these “undruggable” enzymes. To dissect this complexity, we use Metal Fluoride complexes to mimic the pre-hydrolysis state and the transition state of the small G proteins and study these complexes with other techniques including non-natural amino acid incorporation, 19F NMR, 31P NMR, x-ray crystallography, kinetics and QM analysis to investigate the modified catalytic behaviour of these highly dynamic, multi-conformational molecular switches. Our research fills a crucial gap for molecular docking in Ras-targeted drug discovery and presents valuable knowledge for computational investigations, quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD), which can deliver disparate mechanistic and conformational insights.