Cations in charge of RNA folding and function: Realistic modeling and robust predictions

• Applicant: Professorin Dr. Nadine Schwierz, Ph.D.
• Subject Area: Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics ; Biophysics
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 315221747

Metal cations are indispensable for RNA folding and function, two interlinked and vitally important physiological processes. The mechanism by which cations regulate these processes has promising medical and biotechnological applications. Gaining detailed insight allows us to make targeted use of cations to manipulate structure formation, biological function, and even gene expression or to build functional RNA nanomaterial within a cell. In addition, metal cation deficiencies in the metabolic pathway lead to misregulation of vital processes and are associated with severe neurodegenerative diseases and cancer. A fundamental understanding of metal ions and RNA is therefore essential to drive advances in modern medicine and to develop new RNA-based tools for therapeutics.Despite the biological importance, a detailed understanding of the mechanism by which metal cations guide folding into functional structures and control catalytic activity is still lacking. Resolving the role of metal cations is challenging experimentally since the resolution of state-of-the-art techniques is insufficient to characterize the exact interactions. Here, computational methods can contribute important insight. However, these methods are challenged by the requirement to cover a broad range of time and length scales. Up to now, no coherent framework exists that quantitatively describes ion-RNA interactions and robustly predicts the specific influence of different cations on folding and function of RNA. To fill this gap, the proposed work combines state-of-the-art simulation methods and a consistent bottom-up modeling approach as a framework for a thorough understanding of metal cations and RNA. In the proposed work, four models are developed to bridge the time- and length-scale gap. This allows us to provide a comprehensive view of cation-RNA interactions in systems ranging from basic structural motifs to large, biologically relevant and catalytically active RNA macromolecules.Initially, the influence of the four most abundant cellular metal cations on the kinetic folding pathway of RNA is investigated by combining optimized atomistic or newly developed coarse-grained RNA models with powerful sampling techniques. Subsequently, the detailed microscopic ion-RNA interactions are incorporated into a coherent theoretical framework. This connection allows us to determine optimal solvent conditions which yield stable and fully functional RNA structures. Finally, mixed quantum/classical simulations are applied to provide insight into the reaction pathway and the mechanism by which metal cations promote or hinder the biological activity of RNA.In summary, the proposed approach aims to uncover the basic principles for using metal cations to guide folding of RNA into functional structures and to control its biological function in nature and experiment.

• DFG Programme: Independent Junior Research Groups
• Cooperation Partners: Dr. Martin Hengesbach; Professor Dr. Harald Schwalbe