*4 Year MRC PhD Programme* Molecular dynamics analysis of mRNA capping enzymes

The mRNA cap is a structure added to the 5’ end of transcripts which is critical for gene expression, being required for transcript processing and translation initiation. The mRNA cap recruits protein complexes which mediate splicing, export and translation initiation. A series of enzymes catalyze the individual steps of cap synthesis. This project investigates how these enzymes carry out their function and how they are regulated, including the impact of novel co-factors and post-translational modifications. The project involves molecular dynamics simulations of the capping enzymes with Dr Andrei Pisliakov, to provide molecular insights into their functioning mechanisms, in particular atomistic details of activation, regulation, and enzyme catalysis. In silico mutants will be designed to modulate the function of individual enzymes. Larger scale modelling studies will shed light on the organization of and interactions within the capping complexes, comprising various capping enzymes and RNA Pol II. Predictions made on the basis of these simulations will be tested experimentally with Dr Victoria Cowling. Enzyme mutants will be made and their biophysical and biochemical properties investigated. Hypotheses resulting from these experiments will be tested in embryonic stem cells. The study will contribute to a better understanding of the mechanisms of regulated gene expression. The information will help to assess the capping enzymes as drug targets in cancer and parasitic diseases.


The student will work within the laboratories of Drs Pisliakov and Cowling, integrated in the Division of Computational Biology and Centre for Gene Regulation and Expression, and will have an opportunity to master both the ‘wet-lab’ (molecular and cell biology, biochemistry) and ‘dry-lab’ (biomolecular modeling and MD simulations) methods.