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Short Biography
Dr. Esko Oksanen is an expert researcher at the Division of Computational Chemistry at Lund University and an Instrument Scientist at the European Spallation Source. His research focuses on combining experimental structural information with computational techniques to understand enzyme mechanisms.
AMBER postdoctoral fellowship Project (fifth call)
Elucidating the mechanism of triose phosphate isomerase
Triose phosphate isomerase is a key glycolytic enzyme that catalyses a very fast keto-enol isomerisation between glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. Hydrogen atoms play a key role in this remarkably fast process, but they are not detectable by X-ray crystallography. Therefore we have turned to neutron crystallography to locate the hydrogens (Kelpsas et al. 2021) in inhibitor complexes. While knowledge of the protonation states is a prerequisite for mechanistic understanding, computational chemistry methods are crucial for modelling the reaction trajectory. We have previously used quantum mechanics-molecular mechanics (QM/MM) modelling to study the chemical step of the reaction, but our unpublished data from variants suggest modifications to the model we proposed in Kelpsas et al. 2021 that QM/MM is insufficient to describe. Our variant structures also point out a way to determine structures with the substrate dihydroxyacetone phosphate in a way that has previously not been feasible.
In this project – that builds on our existing neutron data – the aim is to determine an X-ray and neutron structure of triose phosphate isomerase in complex with the substrate modifying our existing crystallisation protocols for growing large crystals. The follow-up aim is then to model the reaction trajectory using a combination of QM/MM and empirical valence bond (EVB) methods. The latter allows larger motions than QM/MM to be described while still accurately modelling the chemistry. For the EVB work we will collaborate with the group of Prof Lynn Kamerlin at Georgia Tech (visiting professor at Lund University).
Location: Lund, Sweden
Organisation: Lund University, Faculty of Science, Department of Chemistry
Links
Esko Oksanens profile in Lund University’s Research Portal
The Department of Chemistry’s profile in Lund University’s Research Portal