Branco Weiss Fellow Since
2024
Research Category
Biological Physics
Research Location
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, USA
Background
RNA-RNA interactions are integral to diverse and essential biological processes in cells and in the lab. Mutations affecting these interactions have been linked to devastating human diseases, including neurodegenerative disorders and cancers. Despite their centrality to modern biology, the physical underpinnings of RNA-RNA interactions remain poorly understood. In principle, these interactions are straightforward: if two RNA molecules are complementary, they will hybridize. In practice however, quantitative models predicting interactions in natural settings remain elusive.
There are two main challenges to predicting RNA-RNA interactions: 1) intramolecular secondary structure creates equilibrium and kinetic barriers to intermolecular interactions; 2) RNA-RNA interactions are affected by the presence of other RNA in solution. This first challenge has been explored mostly in its simplest form (strand-displacement reactions); the second remains largely unstudied. Consequently, quantitative models of RNA-RNA interactions typically fail in natural settings.
Details of Research
Dr. Ofer Kimchi’s research program will use transdisciplinary theory-based methods to study RNA-RNA interactions, bolstered by experimental collaborations. These methods include statistical mechanics, dynamical systems theory, information theory, machine learning, and RNA structure prediction. He will focus on the following major questions:
1) Our understanding of complementarity between nucleic acids suggests that nucleic acid molecules should be far more promiscuous than observed in nature. How do nucleic acid molecules limit their interaction partners?
2) In biological settings, RNA molecules frequently form phase-separated condensates. How do nucleic acid-based condensates differ from protein-based condensates? And how can we design nucleic acid molecules to phase separate according to particular phase diagrams?
3) How can the intramolecular structures of nucleic acids be used to control not only the equilibrium properties of their interactions, but their reaction speeds as well?
Ultimately, Dr. Kimchi’s research will explore how biology leverages both its equilibrium properties and its inherent out-of-equilibrium aspects to realize specific RNA-RNA interactions, and to what extent we can implement similar processes in laboratory settings.
