Dynamics, Structure, and Function of Proteins by NMR and Computation

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Critical functions of living systems, such as humans, animals, microbes, and plants, at the microscopic level are often carried out by large biological molecules, which include many different types of proteins. Most proteins adopt multiple shapes (conformations) that incessantly interconvert into each other. The balance between these conformations and their life spans allows proteins to attain properties that are necessary to perform a variety of important biological functions. This includes the specific recognition of large and small molecules for the formation of molecular complexes, including interactions with drugs, the acceleration of chemical reactions, and many other interactions essential for living systems. The project aims at a deeper understanding of these fundamental processes, which will assist the development new cures and the engineering of proteins with new properties. This project provides interdisciplinary training and research opportunities for undergraduate students, graduate students, and postdocs at Ohio State in programs that serve significant numbers of students from demographically underrepresented groups. The new CCIC NMR center will be utilized to introduce a broader public to the discoveries and benefits of basic and applied molecular research. High-school students will have the opportunity to perform and analyze NMR experiments of their own samples. NMR workshops will be organized to introduce and train future NMR users from academia and industries in Ohio. The realistic representation of conformational ensembles of proteins depicting both structure and dynamics at atomistic detail is of fundamental biophysical importance as it provides a better understanding of protein properties and function, such as stability, molecular interactions, recognition, cooperativity, and allostery. During this project, new and broadly applicable methods will be developed for a comprehensive description of the conformational dynamics of globular and intrinsically disordered proteins (IDP) by combining nuclear magnetic resonance (NMR) spectroscopy with advanced computer simulations, and applying these methods to a variety of molecular systems. This includes studies of the allosteric regulation of the sodium-calcium exchanger NCX via its large cytoplasmic loop and the interaction modes of different IDPs with synthetic nanoparticles. New methods for the rapid and simultaneous screening of protein side-chain dynamics on the picosecond-to-nanosecond timescale and the millisecond timescale will be developed and applied to biologically important protein systems. Heterogeneous dynamics behavior observed in protein loops will serve for the systematic improvement of molecular dynamics force fields. The research will produce new experiments, web servers, and software for the more accurate and realistic characterization of proteins in their native environment and their interaction with nanoparticles. The combination of NMR spectroscopy with high-performance computation is expected to become applicable to a wide range of biomolecular systems. These tools will be made available to the structural biology, biophysics, and biomolecular NMR communities. Their application will enhance the understanding of protein behavior and function and serve as input for the engineering of proteins with new properties and the design of better drugs.