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.
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