Next-generation biophysical models for RNA dynamics, ligand binding, and catalysis - ABSTRACT
Structured RNAs play fundamental roles in biological processes and are actively being pursued as targets to
treat disease. Furthermore, synthetic RNA-based biosensors and therapeutics – inspired by natural RNA
machines – are beginning to come online. These RNAs can undergo conformational transitions to bind small
molecules and perform biochemical reactions. Unfortunately, incomplete models of RNA structure and how it
recognizes molecules hinder the development of these potential novel devices and treatments. Without
predictive biophysical models, the field relies on extensive experimental methods to probe RNA 3D structure,
dynamics, and ligand binding. Experiments such as NMR, cryo-electron microscopy, phylogenetic analysis, and
biochemical methods, although powerful, often fail to completely capture an RNA’s structural dynamics and
conformational changes. To address these challenges, the Yesselman Lab is developing novel models of RNA
3D structure and design. We have demonstrated the first high-resolution RNA 3D helical thermodynamics model,
automated design of RNA 3D structure, and developed novel experimental methods to probe secondary and 3D
structures. Over the next five years, the Yesselman Lab aims to improve our understanding and predictive
models of RNA conformational dynamics, RNA-ligand binding, and RNA catalysis: (1) RNA conformational
dynamics: utilizing novel RNA 3D design and massively parallel biochemical assays, our goal is to develop
general models for RNA 3D dynamics to understand better how RNA undergoes conformational transitions and
binds to ligands. (2) RNA-ligand interactions: our goal is to build the first predictive model of RNA/drug
interactions by assaying the effects of small molecule drugs on thousands of RNA structures combined with
novel machine learning approaches. (3) RNA catalytic activity: self-cleaving ribozymes can cut RNA strands.
Compared to proteins, ribozymes are significantly less active. A key difference is ribozymes often have less 3D
scaffolding. When they do, they contain long-range tertiary contacts, but the strength and placement of these
interactions can dramatically affect catalysis activity. Determining the rules of 3D scaffolding in ribozymes will
increase our understanding of RNA catalysis and enable the design of new ribozymes for other catalytic
functions. Findings from these research areas will address challenges and advance knowledge in RNA folding,
molecular recognition, and design. Ultimately, our research program will play a critical role in developing the next
generation of RNA-based diagnostics and therapeutics.
