Postdoctoral position Small Molecules that Repartition RNA Conformational Ensembles

Biotechnology Institute (GBB). The appointment will focus on RNA molecules rarely adopt a single structure. Most fold into an ensemble of interconverting conformations, and the balance between these states is often what determines whether an RNA is translated, spliced, degraded or recognised by its partners. RNA has therefore emerged as a major, largely untapped class of drug targets. Yet despite substantial investment, only one small molecule acting on an mRNA (risdiplam) has reached the clinic, and most compounds identified in binding-based screens have no measurable effect on RNA function. Our recent work suggests why. In a study published in Nature Communications (Zhang et al., 2026), we showed that the FDA-approved anticancer drug mitoxantrone does not simply bind its target RNA: it selectively stabilises one conformation within the RNA’s structural ensemble, repartitioning the population of states and thereby modulating RNA function. Binding to RNA is not enough: changing its shape is what makes a drug work. This points to a different route for RNA-targeted drug discovery, in which compounds are selected not for affinity alone but for their ability to redistribute conformational ensembles in a desired direction. This project will build on that framework. Combining high-throughput RNA structure probing (SHAPE/DMS mutational profiling), ensemble deconvolution, chemical biology and functional assays in cells, the postdoctoral researcher will establish how small molecules reshape RNA conformational landscapes, identify new ensemble-repartitioning compounds, and define the rules that connect a shift in the structural ensemble to a change in RNA function. What are you going to do? As a postdoctoral researcher you will: Map how small molecules reshape RNA conformational ensembles using chemical probing (SHAPE/DMS-MaP) of RNA–ligand complexes in vitro and in cells, combined with ensemble deconvolution to resolve individual conformers and quantify ligand-induced repartitioning. Screen and characterise ensemble-repartitioning compounds, moving beyond affinity-based readouts to identify molecules that shift the balance between functional and non-functional RNA states on disease-relevant targets. Dissect mechanism by defining binding sites, ligand selectivity for individual conformers and the thermodynamic and kinetic basis of ensemble repartitioning, in collaboration with chemistry and structural biology partners. Link structure to function through reporter assays, translation and splicing readouts, and transcriptome-wide structure probing to assess on-target effects and selectivity in cells. Develop methods and analysis pipelines for the quantitative, high-throughput profiling of ligand-induced changes in RNA structural ensembles, contributing to the lab’s open-source software ecosystem. Publish and present your findings in peer-reviewed journals and at international conferences, and contribute to supervising PhD and MSc students in the lab. Requirements We are seeking a curious, focused, and collaborative researcher who thrives on challenges. You will be a strong candidate if you have: A PhD in Molecular Biology, Biochemistry, Chemical Biology, Biophysics, RNA Biology, Bioinformatics or a related field, completed or nearly completed. Hands-on experience with RNA biochemistry and/or RNA structure probing (e.g. SHAPE, DMS, mutational profiling, next-generation sequencing library preparation) is a strong advantage. Experience with small-molecule/RNA interactions, chemical biology, compound screening or biophysical binding assays is highly desirable. Familiarity with computational analysis of sequencing data (Unix/shell, Python or R); experience with RNA structure prediction or ensemble analysis is a plus. Candidates with a primarily computational background and a strong interest in experimental validation are also encouraged to apply. A strong record of scientific output relative to career stage (publications, conference contributions). Enthusiasm for interdisciplinary, collaborative science and willingness to interact closely with chemists and structural biologists within and outside Groningen. Good written and spoken English, strong communication, organisational and mentoring skills. Conditions of employment Fixed-term contract: A fixed-term contract of 1.0 FTE for the duration of 12 months. Salary indication: €4251—€4422 per month. Weekly hours: 38 hours per week. What can you expect from us? 232 vacation hours per year, based on a 38-hour workweek (1.0 FTE). You can also work more or fewer hours in exchange for more or fewer free hours. For example, with a 40-hour workweek, you save 96 extra free hours, and with a 36-hour workweek, you lose 96 hours. End-of-year bonus of 8.3% and 8% holiday allowance. Extensive opportunities for personal and professional development. Employer University of Groningen At the University of Groningen (UG), researchers from all fields of academia and technology are working on academic challenges and societal questions. Lecturers prepare their students for meaningful careers within or outside the academic world. Interdisciplinary research and teaching, sharing of knowledge, collaboration with businesses, government institutions, and societal organizations are aspects that are of the utmost importance to this European top university. The UG aims to be an open academic community with an inclusive and safe working climate that invites you to add your value. Department Faculty of Science and Engineering The Faculty of Science and Engineering (FSE) provides teaching and research across a wide range of disciplines, from physics and biology to artificial intelligence, mechanical engineering, and pharmacy. In close collaboration with partners from industry, healthcare, and society, we contribute to the urgent challenges of our time, such as energy, sustainability, digitization, and medical technology. Our community is open and informal, with more than 7,000 students, 1,000 PhD students, and 1,400 staff members from all over the world. If you would like to learn more about the Faculty of Science and Engineering, visit rug.nl/fse. The RNA Structural Dynamics Group at the Groningen Biomolecular Sciences and Biotechnology Institute (GBB) is looking for a talented and motivated postdoctoral researcher to lead this line of research. The lab develops and applies experimental and computational methods for mapping RNA structure and dynamics directly in living cells, including chemical probing coupled to mutational profiling and high-throughput sequencing, the deconvolution of heterogeneous RNA structural ensembles, and sequencing-base RNA structure and modification profiling. Over the past years we have used these approaches to uncover conserved RNA regulatory switches, to chart the complexity of cellular RNA folding, and, most recently, to characterise how small molecules such as mitoxantrone redistribute RNA conformational ensembles. You will work at the interface of RNA structural biology, chemical biology and drug discovery, with access to the lab’s complete pipeline from compound screening and structure probing through to computational ensemble analysis and functional validation. Additional information Do you have any questions or need more information? Questions about the content of the job? Danny Incarnato (Associate Professor): D.Incarnato@rug.nl Questions about your application process? Chienes Metus (Managing Coordinator): A.Metus@rug.nl