PROBING THE INFLUENCE OF ARGININE METHYLATION ON THE MODULATION OF BIOMOLECULAR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细胞利用微弱的生物相互作用来控制大量的生物过程。从人类健康的角度来看，如果不能准确控制这些相互作用，可能会导致多种疾病，从癌症到普恩病毒疾病，再到自闭症。已有研究表明，在细胞核区发现的许多蛋白质，特别是那些与核酸结合的蛋白质，都经历了一种称为精氨酸甲基化的翻译后修饰。这表明精氨酸甲基化被用来调节基因表达，可能是通过改变修饰蛋白与核酸和其他基因表达蛋白/辅因子的结合亲和力。精氨酸甲基化蛋白对核酸结合的能量学和几何构型的影响的大小尚不清楚。在这个子项目中提出的研究旨在了解精氨酸甲基化对控制蛋白质DNA和蛋白质相互作用的影响。为此，将制备一些基于小分子、多肽和蛋白质的模型，这些模型可以结合1)核酸和2)含有胍基(精氨酸残基的官能团)。鸟嘌呤基团将被顺序甲基化，这对这些模型化合物的DNA结合性质、DNA蛋白质络合物的后续结构以及DNA蛋白质结合作用的强度的影响将被确定。此外，还将利用高级电子结构计算方法对这些研究的结果进行合理化，并指导DNA结合模型化合物的制备。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cells utilize weak biological interactions to control a multitude of biological processes. From a human health standpoint a failure in the precise control of these interactions can lead to a number of diseases ranging from cancer to prion diseases to autism. It has been shown that many proteins found in the nuclear region of cells, especially those that bind nucleic acids, undergo a post translational modification called arginine methylation. This indicates that arginine methylation is utilized to modulate gene expression, possibly by changing the binding affinity of the modified protein towards nucleic acids and other gene-expression proteins/cofactors. The magnitude of the change in the energetics and geometries of nucleic acid binding effected by arginine methylated proteins is poorly understood. The research proposed in this subproject is aimed at understanding the influence that arginine methylation has on controlling protein DNA and protein protein interactions. To these ends a number of small molecule, peptide, and protein based models that can bind 1) nucleic acids and 2) contain guanidinium-groups (the functional group of an arginine residue) will be prepared. The guanidinium group will be sequentially methylated, and the influence this has on the DNA binding properties of these model compounds, the subsequent structure of the DNA protein complex, and the strength of the DNA protein bonding interaction will be determined. In addition, high-level electronic structure computational methods will be utilized to both rationalize the results obtained from these studies and guide the preparation of the DNA-binding model compounds.