Topics in protein and RNA folding and dynamics

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Devarajan (Dave) Thirumalai is supported by an award from the Chemical Theory, Models and Computational Methods program in the Chemistry Division to develop novel theory and computational methods to understand how proteins and ribonucleic acids (RNA) get their shapes, and how these shapes affect their interaction with other substances. Proteins and RNA are among the most important molecules of life. They carry out all the functions in cells by adopting specific shapes and through mutual interactions. In a third project, Dr. Thirumalai uses modern theoretical and computational tools to decipher how molecular motors transport cargo by walking on polar tracks. Such transport is required for cells to function properly. Thus, fundamental principles of chemistry and physics are used to describe the molecular basis of the translation of cellular information, resulting in increased understanding of essential biological processes. The Biophysics program in the Division of Molecular and Cellular Biology and the Physics of Living Systems program in the Physics Division contribute equally to this award. In addition to students and postdoctoral associates, undergraduates from several universities contribute to these projects. In order to attain the broad goals outlined above, Dr. Thirumalai addresses key questions in three areas. (1) Protein Folding: In order to function, proteins must fold to a compact three-dimensional shape, which is specified by the primary sequence of amino acids. It is suspected that the initial step in this process is the collapse of the chain from an extended state although the conclusions based on different experiments vary. In order to resolve this important controversy, Dr. Thirumalai will use fully atomistically-detailed simulations of both model systems and proteins to dissect the nature of the collapse process. (2) RNA folding: In contrast to protein folding, little is known about RNA folding. These highly charged molecules, built from four nucleotides, require cations to fold. Thirumalai develops new models to describe how these cations interact with RNA to facilitate their folding. This project combines analytical theory with novel computational methods. (3) Molecular Motors: kinesin, dynein, and myosin are motors that transport cargo across microtubules and actin, which are polar tracks. Many beautiful single molecule experiments have shown that they walk hand-over-hand across these tracks. The molecular basis of this motion is not fully understood. Dr. Thirumalai develops new models to simulate their movements in order to illustrate the coupling between the internal dynamics and the motility. In addition, he and his coworkers explore the design of the lever arm to explore the robustness of their motions on the polar tracks.