Dynamics and Energetics of Rare Conformational Transitions in RNA

Ribonucleic acids (RNAs) are conformationally dynamic molecules that play an important role in different cellular processes as well as in the development of various diseases. The biophysical processes underlying RNA dynamics are often associated with rare structural transitions that are crucial to correct RNA functioning. However, despite recent advancements in structure determination techniques which provide insights into the dynamics and interactions in RNAs, the characterization of these structural transitions in RNA remain challenging due to the dynamic nature of RNA and the limitations in capturing all details at the atomic level. In this work, atomistic simulations were utilized to better understand various biophysical processes which govern RNA dynamics and function. Specifically, non-equilibrium steered molecular dynamics simulations were utilized to characterize the (un)binding process of several inhibitors from viral RNA elements, revealing that a series of rare base flipping events and salt-bridging interactions contribute to the recognition of ligands. The base flipping mechanism was further characterized using a path sampling technique establishing a refined reaction coordinate which describes the relative position of the flipping base with respect to the neighboring bases. Lastly, the energetics and dynamics of methylation, the most abundant chemical modification in RNA, on an RNA hairpin capped by a methylated tetraloop motif was studied using alchemical free-energy calculations, revealing enhanced flexibility upon methylation.