Molecular Dynamics Simulations of Chemically Modified Ribonucleotides

Post-transcriptional modifications are crucial for RNA function, with roles ranging from the stabilization of functional RNA structures to modulation of RNA–protein interactions. Additionally, artificially modified RNAs have been suggested as optimal oligonucleotides for therapeutic purposes. The impact of chemical modifications on secondary structure has been rationalized for some of the most common modifications. However, the characterization of how the modifications affect the three-dimensional RNA structure and dynamics and its capability to bind proteins is still highly challenging. Molecular dynamics simulations, coupled with enhanced sampling methods and integration of experimental data, provide direct access to RNA structural dynamics. In the context of RNA chemical modifications, alchemical simulations where a wild type nucleotide is converted to a modified one are particularly common. In this Chapter, we review recent molecular dynamics studies of modified ribonucleotides. We discuss the technical aspects of the reviewed works, including the employed force fields, enhanced sampling methods, and alchemical methods, in a way that is accessible to experimentalists. Finally, we provide our perspective on this quickly growing field of research. The goal of this Chapter is to provide a guide for experimentalists to understand molecular dynamics works and, at the same time, give molecular dynamics experts a solid review of published articles that will be a useful starting point for new research.