Molecular dynamics analysis of mRNA capping: Characterising the activation mechanisms of the mammalian capping enzymes

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mRNA capping is vital for the regulation of genes in eukaryotic organisms. This capping is activated downstream of c-Myc, a major oncoprotein overexpressed in over 50% of human cancers, therefore, mRNA capping is a promising target for cancer therapeutics. The Capping Enzyme carries out the first two steps in this process. Many questions remain about its activation and regulation, limiting our ability to design drugs that target it. It is activated by binding to the phosphorylated C-terminal Domain of RNA Polymerase II. However, the molecular details of this activation mechanism have been elusive using conventional biochemical techniques.I will address this problem from a new angle by using molecular dynamics simulations to study the conformational changes that occur upon C-terminal Domain binding. Further computational and biophysical analysis will be performed to characterise the interaction surface and catalytic core. An interdisciplinary collaboration with the Cowling lab will yield experimental evidence to support these findings.Key Words and Skills:Questions:1. Explain interdisciplinary interface: Yes, it talks about collaboration between computational biophysics and experimental biology2. Does project require significant amount of quantitative skills? YES3. Does project require significant amount of whole organism physiology skills? NO