Correlated Motions of Folded and Non-Folded Proteins by NMR Spectroscopy and Computation

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Detailed information on protein dynamics at an atomic level is of fundamental biophysical importance for understanding protein stability and function. The overall goal of this research is the exploration and development of new methods for a comprehensive description of complex dynamics of folded and non-folded protein systems and to demonstrate their applicability to biologically important systems. Natively unfolded proteins play a vital role in a wide range of biophysical and biochemical processes. Recent analysis of NMR residual dipolar coupling measurements of unfolded proteins suggest that these states can be well characterized by conformational ensembles that are locally biased in their backbone dihedral angles as a function of the amino-acid types. This project will analyze a large variety of such ensembles by statistical methods that assess the internal translational and reorientational correlation behavior. This analysis will be linked to dynamic NMR parameters and thermodynamic properties. Comparison with the folded state behavior will give useful insights into determinants of protein stability. Motional modes in proteins often exhibit a collective character. The nature of these motions and their entropic implications will be explored in view of recent experimental NMR residual dipolar coupling and relaxation data as well as advances in conformational sampling methods and simplified descriptions in terms of reorientational elastic network models. NMR experiments will be performed on the protein MDM2 and its interactions with other polypeptides. This project will produce new computational, statistical mechanical, and NMR spectroscopic concepts for the characterization of folded and non-folded protein states, which will enhance the understanding of protein behavior and function and serve as input for the engineering of proteins with new properties. The project will provide interdisciplinary training and research opportunities for graduate students and postdoctoral researchers, including students from demographically underrepresented groups, including female, African-American, Native American Indian, Hispanic, and (US) Asian/Pacific Islander graduate students. Research methods and results will be incorporated into advanced undergraduate and graduate courses on biophysics and biomolecular spectroscopy. The PI will participate in NHMFL's strong outreach programs for high school and junior college students and a summer undergraduate research program. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Experimental Physical Chemistry Program in the Division of Chemistry in the Mathematical and Physical Sciences Directorate.