This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)
Detailed information on protein dynamics at an atomic level and its thermodynamic implications is of fundamental biophysical importance for understanding protein stability and function. The overall goal of the project is the development of new methods for a comprehensive description of complex dynamics and thermodynamics of proteins and to demonstrate their applicability to biologically important molecular systems. The recent advent of increasingly long molecular dynamics simulations will be used to close the time-scale gap between simulations and experimental nuclear magnetic resonance (NMR) parameters, in particular residual dipolar couplings and rotating frame relaxation rates. Very long simulations into the ms range will be performed to make quantitative comparisons with experiment both for the protein backbone and the side chains. This information, on the one hand, will yield a comprehensive assessment of the accuracy of molecular mechanics force fields and guide their further optimization. On the other hand, it provides a realistic microscopic approach to the interpretation of these experimental NMR parameters. These simulations also allow analysis of statistically significant correlated motions between soft degrees of freedom, such as dihedral angles, and thereby permit the accurate extraction of configurational entropies. These concepts will be tested on model protein systems and applied to the experimental and computational analysis of the entropy transfer mechanism of the protein MDM2 when it interacts with inhibitors.
The results of this research will produce new computational, statistical thermodynamic, and NMR spectroscopic concepts for the characterization of proteins, which will enhance the understanding of protein behavior and function and serve as input for the engineering of proteins with new properties. The results will be disseminated in form of publications and will be made available to the biophysics and biomolecular NMR communities in terms of public web servers. The project provides interdisciplinary training and research opportunities for graduate students at the Department of Chemistry and Biochemistry at Florida State University (FSU), at the Institute of Molecular Biophysics at FSU, and at the National High Magnetic Field Laboratory (NHMFL), which count significant numbers of students from demographically underrepresented groups. Research methods and results will be incorporated into advanced undergraduate and graduate courses on biophysics and biomolecular spectroscopy. The P.I. participates in NHMFL's strong outreach programs for undergraduate and graduate students and at the annual Open House, which is open to the public.
