With this award, the Chemistry of Life Processes Program in the Division of Chemistry is funding Dr. Junji Iwahara of the University of Texas Medical Branch (UTMB)-Galveston to study the roles of the ion-pair dynamics in protein-DNA association. The work is collaborative with Dr. B. Montgomery Pettitt from UTMB-Galveston and Dr. David Gorenstein from UTHSC-Houston. The team will study the ion-pair dynamics for lysine and arginine side chains interacting with DNA phosphate groups in the HoxD9 homeodomain-DNA complex. The central hypothesis in this research project is that by allowing high mobility of involved atoms, the ion-pair dynamics are entropically important for protein-DNA interactions. The research team will test this hypothesis by using approaches of NMR spectroscopy, biophysical chemistry, organic chemistry, and computational chemistry. Three specific objectives to be pursued are: 1) characterizing the dynamics of intermolecular ion pairs between protein and DNA, 2) delineating motional changes of protein side-chain cations due to ion-pair formation with DNA, and 3) elucidating the mechanism by which oxygen-to-sulfur substitution in DNA phosphate enhances protein-DNA affinity. By providing the atomic-level information on the ion-pair dynamics at the biologically important macromolecular interfaces, this project will substantially deepen our understanding of ion pairs and their roles in protein function.
Despite the universal importance of ion pairs in chemical and life sciences, dynamic properties of the ion pairs in life processes such as molecular recognition and catalysis are not well understood. This project aims to shed light on this fundamental problem, with a particular focus on ion pairs between protein and DNA. By unraveling the dynamics of these intermolecular ion pairs and their entropic effects on macromolecular association, this project is expected to facilitate the engineering of proteins and/or nucleic acids. The experimental data on the ion-pair dynamics for the relatively small protein-DNA complex will allow the computational chemistry community to validate and improve the molecular dynamics force fields. Moreover, in this project, research activities will be integrated into several educational/outreach activities. The PI will organize an NMR seminar series and a local NMR workshop for the Gulf Coast Consortium comprising scientists in the Greater Houston area. Results from this project are to be incorporated into an interdisciplinary course being developed by the PI, and outreach to high school students in the area is planned.
