(746f) Simulation Methods to Probe RNA Conformational Dynamics

Since the seminal discovery that Ribonucleic acid (RNA) molecules can catalyze complex reactions similar to proteins, their functional repertoire has dramatically expanded with fundamental roles in many regulatory processes such as gene expression and control. RNA therefore is no longer considered a passive information carrier, but rather a molecule with versatile chemical and physical properties that can be exploited in therapeutic and engineering applications. Underlying such applications, one ubiquitous and critical physical attribute is dynamics encompassing a large number of modes and spanning vast spatiotemporal scales. Dynamics in RNA are intimately connected to intrinsic structural features (e.g. base-pairing) as well as extrinsic factors (e.g. ligand binding). While equilibrium fluctuations in biomolecules such as RNA are inherent, it is the large-scale conformational transitions that play a dominant role in interfacial processes such as biomolecular recognition. The information on such conformational states is encoded in the physical free energy landscapes of RNA molecules, the robust sampling of which can provide key thermodynamic and kinetic information on functional conformational ensembles. In this talk, we will present applications of new and emerging enhanced sampling molecular simulation methods based upon all-atom and structure-based models of small RNA molecules that are known to undergo large-scale conformational changes. A specific example that will be highlighted is of the transactivation response element RNA (TAR-RNA) from the genome of HIV-1 virus possessing versatile conformational states that are rapidly becoming targets of novel therapeutics.