MD and MC Studies of Hu and IHF Complexes with Unusual Forms of DNA

描述(由申请人提供)：拟议的奖学金研究的目标是利用计算生物物理学的理论和方法阐明真细菌蛋白HU和IMF对不寻常形式的DNA的复杂形成。需要考虑的特定系统包括与高度弯曲的DNA双螺旋结合的蛋白质，这些DNA双螺旋在转录调控、位点特异性重组和复制启动中发挥作用，以及当DNA进行基因重组时形成的四向Holliday连接。要使用的具体方法是计算密集型分子动力学和蒙特卡罗模拟，这些方法需要超级计算机设备。在能量和力的计算中，蛋白质、DNA、溶剂水和实验盐条件将用离散的全原子模型来处理。HU-和IHF-DNA 复杂的形成在很高的计算精确度水平上，在这个过程中，能够根据作用于关键节点的化学力来分析结合的自由能。这项研究中获得的新知识将为解释实验结果和在亚分子水平上理解这些生物过程的作用机制提供基础。 与公共健康相关：特殊蛋白质激活DNA并促进基因表达。这项提议的目标是使用现代计算技术来了解这些蛋白质如何与DNA相互作用。了解对这些相互作用的控制对于开发用于抗击疾病的药物至关重要。

DESCRIPTION (provided by applicant): The objective of the proposed fellowship research is to elucidate the complex formation of the eubacterial proteins HU and IMF to unusual forms of DNA using the theory and methodologies of computational biophysics. Specific systems to be considered involve the proteins binding to highly bent forms of the DNA double helix that play a role in transcriptional regulation, site specific recombination and the initiation of replication, and to the four-way Holliday junction formed when DNA undergoes genetic recombination. The specific methods to be used are computationally intensive molecular dynamics and Monte Carlo simulations which require supercomputer facilities. The proteins, DNA, solvent water, and experimental salt conditions will be treated with a discrete all-atom model in the calculation of energies and forces. HU- and IHF-DNA complex formation at a high level of computational rigor and, in the process, enables the analysis of the free energy of binding in terms of the chemical forces acting at critical junctures. The new knowledge obtained in this research will provide a basis for the interpretation of experimental results and an understanding of the mechanisms of action in these biological processes at the sub-molecular level. PUBLIC HEALTH RELEVANCE: Special proteins activate DNA and facilitate gene expression. The goal of this proposal is to use modern computational techniques to learn how these proteins interact with DNA. Understanding the control over these interactions is critical in the development of agents used to fight disease.