Ribonucleic acid (RNA) plays a pivotal role in cellular functions, from gene regulation to protein synthesis. Despite its relatively simple structure, RNA exhibits a remarkable diversity in its functions. A recent study by researchers at Pennsylvania State University sheds light on one aspect of this versatility: the “shifted wobble” in RNA’s molecular structure.
Saon, M. S., Douds, C. A., Veenis, A. J., Pearson, A. N., Yennawar, N. H., & Bevilacqua, P. C. (2025). Identification and characterization of shifted G•U wobble pairs resulting from alternative protonation of RNA. Nucleic Acids Research, 53(14). https://doi.org/10.1093/nar/gkaf575
The Penn State team, led by Professor Philip Bevilacqua, utilized cheminformatics to analyze over 3,000 high-resolution RNA structures. Their findings revealed that in some cases, the G-U wobble adopts an alternative conformation, termed the “shifted wobble,” where the G base resides in the major groove of the RNA helix. This shift requires specific protonation states of the bases involved.
Traditionally, RNA’s base pairing follows the standard Watson-Crick model, where guanine (G) pairs with cytosine (C), and adenine (A) pairs with uracil (U). However, in certain regions, G can pair with U, forming what is known as a “wobble” base pair. In these instances, the G and U bases are positioned differently compared to the canonical G-C pairing.
Philip Bevilacqua professor at Eberly College of Science at Penn State stated,
“It can catalyze reactions as an enzyme, act as a small molecule sensor or provide structure to cellular organelles. This functional diversity has led to the hypothesis that RNA might have been key to origins of life on Earth, but the question remains: ‘How is RNA so functionally versatile given its limited molecular diversity?'”
This structural variation suggests that RNA molecules can adopt multiple conformations, potentially influencing their functional roles within the cell. The shifted wobble may contribute to the molecular diversity observed in RNA’s functions, such as catalyzing reactions or serving as a structural component of cellular organelles.
Furthermore, the study indicates that these shifted wobble pairs are more prevalent in bacterial RNA compared to eukaryotic RNA. This observation opens avenues for targeted therapeutic interventions, as drugs designed to interact with these unique RNA structures could potentially disrupt bacterial functions while minimizing effects on human cells.
The research team aims to expand upon these findings by exploring other non-covalent modifications in RNA structures. Understanding these variations could provide deeper insights into RNA’s functional versatility and its potential as a target for therapeutic strategies.
This study underscores the importance of structural nuances in biomolecules and their impact on biological functions. As our understanding of RNA’s structural diversity grows, so does the potential for innovative approaches in medicine and biotechnology.
Adrian graduated with a Masters Degree (1st Class Honours) in Chemical Engineering from Chester University along with Harris. His master’s research aimed to develop a standardadised clean water oxygenation transfer procedure to test bubble diffusers that are currently used in the wastewater industry commercial market. He has also undergone placments in both US and China primarely focused within the R&D department and is an associate member of the Institute of Chemical Engineers (IChemE).
