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

mRNA capping在真核生物基因调控中起着至关重要的作用。mRNA capping在c-Myc下游被激活，c-Myc是一种主要的癌蛋白，在超过50%的人类癌症中过表达，因此，mRNA capping是癌症治疗的一个有希望的靶点。封盖酶执行这个过程的前两个步骤。关于它的激活和调节还有许多问题，这限制了我们设计针对它的药物的能力。它通过与RNA聚合酶II的磷酸化c端结构域结合而激活。然而，这种激活机制的分子细节使用传统的生化技术一直难以捉摸。我将从一个新的角度来解决这个问题，利用分子动力学模拟来研究c端结构域结合时发生的构象变化。进一步的计算和生物物理分析将进行表征的相互作用表面和催化核心。与考林实验室的跨学科合作将产生实验证据来支持这些发现。关键词：技能；问题：解释跨学科的界面：是的，它讨论了计算生物物理学和实验生物学之间的合作。项目是否需要大量的定量分析技能？YES3。项目是否需要大量的整体生理技能？否

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