Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

20-POS Board 20 Insight into Oxygen Diffusion in Oxygenases Carmen Domene , Kings College London, London, United Kingdom.

The 2-oxoglutarate (2OG) dependent oxygenases are a superfamily of non-haem iron dependent oxygenases, most of which use the Krebs cycle intermediate, 2-oxoglutarate (2OG), as a cosubstrate. We are interested in understanding these enzymes for their ability to catalyse synthetically difficult or ‘impossible’ reactions (e.g. the stereoselective hydroxylation of unactivated carbon-hydrogen bonds), for their diverse physiological roles, and for their links to disease. These enzymes have important roles in oxygen sensing, collagen biosynthesis, fatty acid metabolism and in the epigenetic regulation of gene expression. There are estimated to be 60-80 human 2OG oxygenases. Defining functions for all human '2OG oxygenases' at biochemical, cellular, and physiological level is crucial. Given the mechanistic and structural conservation amongst 2OG oxygenases, we are attempting to define the molecular features that are responsible for their reaction with O 2 . As part of this, a combined computational and experimental approach has been followed. Crystal structures have been obtained, small- molecule inhibitors of 2OG oxygenases have been identified, and computational mechanistic studies using equilibrium and non-equilibrium computer simulations have been carried out. An overview of this project will be given in this presentation.

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