Cations in charge of RNA folding and function
Project of the Research Lab of Nadine Schwierz
Mechanism of peptide adsorption and adsorption resistance
Metal cations are indispensable for RNA folding and function, two interlinked and vitally important physiological processes. Gaining detailed insight allows us to make targeted use of cations to manipulate structure formation, biological function, and even gene expression. In addition, metal cation deficiencies 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.
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. Our 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. 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.
Optimized force fields for mono- and divalent metal cations
In order to capture the mechanism by which different cations influence RNA folding and function, an accurate parametrization for the cations is crucial. We have systematically optimized the force field parameters for eight different mono- and divalent metal cations including Li+, Na+, K+, Cs+, Mg2+, Ca2+, Sr2+, and Ba2+. Our optimized parameters represent a robust and efficient model to quantitatively capture ion specific binding affinities, ion binding kinetics, and ion competition.
RNA and the Hofmeister series
A large variety of physicochemical properties involving RNA depends on the type of metal cation present in solution. All-atom molecular dynamics simulations allow us to gain microscopic insight into the origin of these ion specific effects. Our results reveal that binding sites involving phosphate groups preferentially bind metal cations with high charge density (such as Mg2+) in inner-sphere conformations while binding sites involving N7 or O6 atoms preferentially bind cations with low charge density (such as K+). The binding affinity therefore follows a direct Hofmeister series at the backbone but is reversed at the nucleobases.
Coarse-grained model for double-stranded RNA
We have recently developed a coarse-grained description of double-stranded RNA based on quantum-mechanical calculations. The structural and mechanical properties of the coarse-grained model are in good agreement with experimental data. The model is computationally efficient and allows us to extend the time- and length scales accessible by computer simulations.