Topics in Protein and RNA Folding and Dynamics

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With support from the he Chemical Theory, Models and Computational Methods program in the Division of Chemistry (CHE) and the Molecular Biophysics program in the Division of Molecular and Cellular Biosciences (MCB), Professor Devarajan Thirumalai of the University of Texas at Austin will study the ways that proteins and RNA interact with each other to control a number of biophysical processes. In addition to DNA, which contains the blueprint of life, a myriad of cellular activities are determined by the diverse shapes and conformations that proteins and RNA adopt in different environments. Professor Thirumalai will develop new computational methods for simulating the molecular factors that determine droplet formation in disordered proteins and the mechanisms by which RNA molecules, previously thought to be merely passive carriers of informations, self-organize to form condensates. Professor Thirumalai will also work to develop both a theoretical framework and simulation methods to understand the molecular basis by which molecular motors, which carry cargo in cells, take multiple steps on polar tracks. These studies have the potential to provide a higher level of molecular understanding of complex biomacromolecular processes of relevance in biophysics. The research project will involve training students and postdoctoral fellows in interdisciplinary research areas, and will likely have broad impact in related areas in chemistry and the study of complex biochemical systems.In this project, the Thirumalai research team will create new coarse-grained models and computational tools to investigate (i) the conformational ensembles of intrinsically disordered proteins (IDPs), (ii) RNA folding, and (iii) the stepping mechanism of kinesin motors. The research team will employ multiscale simulations to investigate the effects of phosphorylation at specific sites on the assembly of fibril-forming IDPs along with the impact of crowded cellular environments on protein function. Regarding RNA folding, Professor Thirumalai will develop computational tools to account for multivalent ions ions, complimented by polyelectrolyte theories, and describe the thermodynamics and kinetics of folding of ribosomal RNAs. New methods to understand the mechanisms of cation-driven droplet formation and the associated dynamics in low complexity RNA sequences will likewise be devised. Finally, the stepping of kinesin on a microtubule (MT) will be simulated to address fundamental questions regarding the symmetry of the motor head motions: whether the detached kinesin motor passes the MT bound motor always on one side (symmetric walk) or alternates between two sides (asymmetric walk). In order to answer this and related questions, new models will be used to simulate multiple steps that kinesin takes on a MT. The software developed in these studies for exploring complex systems of biological importance will be made available for distribution.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.