Researchers advance RNA medical discovery decades ahead of schedule

Ribonucleic acid, commonly known as RNA, is involved in many biological functions, and some, including gene silencing, are utilitized to cure diseases. RNA has recently gained attention as a promising drug target. Unfortunately, only a small fraction of RNA structures have been determined experimentally, and the process of uncovering these structures requires significant time and effort. Using this time scale, the structures of many life saving RNA may not be discovered for years. As a result, there is a significant gap between the types of known RNA and the available structural data.

Researchers at Purdue University have developed a computational solution to this problem named NuFold, which will model 3D RNA structures that could expedite medical discovery decades ahead of schedule. The research team, led by Daisuke Kihara, professor of biological sciences and computer science in the Purdue College of Science, published their findings in Nature Communications.

This result has wide-ranging potential applications, such as in understanding RNA mechanisms and in drug development for diseases involving RNA. NuFold’s code and Google Colab notebook are publicly available, making it accessible not only to researchers but also to anyone interested in RNA structural models. NuFold is a groundbreaking tool for more accurate and efficient RNA structure prediction, with the potential to significantly advance RNA research.

In order to sustain life, varieties of molecules need to work together. Proteins in these molecules have typically been the primary focus of research, but recently RNA has been found to play unique and broad roles in essential life functions. To understand how RNA functions, it is essential for scientists to know its 3D structure.

Kihara studies protein tertiary structure prediction/comparison, protein-protein docking, protein-ligand docking, protein function prediction, protein sequence analysis, and metabolic/regulatory pathway analysis in the Structural Biology Group within the Department of Biological Sciences. His team is affiliated with the Purdue Institute for Cancer Research and also works closely with the Rosen Center for Advanced Computing (RCAC).

“NuFold is the RNA equivalent of AlphaFold. AlphaFold is the computational protein structure prediction method, which got the Nobel Prize in chemistry in 2024,” said Kihara. “AlphaFold is now routinely used in many biology labs. NuFold would be an RNA version of AlphaFold.  So, in a way, we’re extending the breakthrough of AlphaFold into the world of RNA, which has been much more challenging to tackle. By modeling RNA's 3D structure, we can help bridge the gap created by the lack of experimentally determined structures, advancing research on RNA and its crucial roles in life and health.”

“It took over three years to develop NuFold,” said Yuki Kagaya, main developer of NuFold and postdoctoral research assistant at Purdue. “A key feature of NuFold is how it represents RNA internally, considering the base pairs that are pivotal to the structure while accurately capturing RNA's inherent flexibility. In benchmark tests, NuFold has outperformed traditional energy-based methods and shown better accuracy in local structure prediction compared to recent deep learning-based approaches.”

NuFold will help researchers “visualize” how RNA structure would look and boost research progress and drug development with RNA.

“To solve problems that cannot be immediately addressed through experiments, we developed NuFold as a computational solution,” said Kihara. “NuFold can help bridge the gap by predicting the 3D structures of RNA from its sequence. By leveraging state-of-the-art machine learning techniques, NuFold can predict the full atomic structure of RNA given its sequence.”

The research authors are all affiliated with Purdue. Kihara is the lead author, who conceived of and directed the study. Other authors include Kagaya, Zicong Zhang (graduate student, computer science), Nabil Ibtehaz (graduate student,computer science), Xiao Wang (former graduate student, computer science), Tsukasa Nakamura (postdoc, biological sciences) and Pranav Deep Punuru (undergraduate student, biological sciences).  Kagaya is the main developer, and the rest of the team participated in coding and benchmarking and developing the Google Colab web server.

“The current research was a team effort within our lab, bringing together students and postdocs in computer science and biology. It was enabled by computer resources at RCAC, Purdue the NSF XSEDE (now ACCESS, or Advanced Cyberinfrastructure Coordinator Ecosystem) program and also received support from the Oracle for Research Cloud Grant,” said Kihara.

This work is supported in part by the National Institutes of Health (R01GM133840, R01GM123055) and the National Science Foundation (CMMI1825941, MCB1925643, IIS2211598, DMS2151678, DBI2003635, and DBI2146026). A part of the computation in this work was performed with support from Oracle for Research Cloud Grant (CPQ-3035339), and Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1548562.

About the Department of Biological Sciences at Purdue University

The Department of Biological Sciences is the largest life sciences department at Purdue University. As part of Purdue One Health, we are dedicated to pioneering scientific discoveries and transformative education at the cutting edge of innovation. From molecules to cells, from tissues to organisms, from populations to ecosystems — we bring together multiple perspectives, integrating across biological scales to advance our understanding of life and tackle the world’s most pressing challenges. Learn more at bio.purdue.edu.

About the Department of Computer Science at Purdue University 

Founded in 1962, the Department of Computer Science was created to be an innovative base of knowledge in the emerging field of computing as the first degree-awarding program in the United States. The department continues to advance the computer science industry through research. US News & World Report ranks the department No. 8 in computer engineering and No. 18 and 19 overall in undergraduate and graduate computer science. Additionally the program is ranked No. 6 in cybersecurity, No. 8 in software engineering, No. 13 in systems, No. 15 in programming languages and data analytics, and No. 18 in theory. Graduates of the program are able to solve complex and challenging problems in many fields. Our consistent success in an ever-changing landscape is reflected in the record undergraduate enrollment, increased faculty hiring, innovative research projects, and the creation of new academic programs. The increasing centrality of computer science in society, academic disciplines and new research activities—centered around foundations and applications of artificial intelligence and machine learning, such as natural language processing, human computer interaction, vision, and robotics, as well as systems and security—are the future focus of the department. Learn more at cs.purdue.edu.

About Purdue University 

Purdue University is a public research university leading with excellence at scale. Ranked among top 10 public universities in the United States, Purdue discovers, disseminates and deploys knowledge with a quality and at a scale second to none. More than 107,000 students study at Purdue across multiple campuses, locations and modalities, including more than 58,000 at our main campus in West Lafayette and Indianapolis. Committed to affordability and accessibility, Purdue’s main campus has frozen tuition 13 years in a row. See how Purdue never stops in the persistent pursuit of the next giant leap — including its comprehensive urban expansion, the Mitch Daniels School of Business, Purdue Computes and the One Health initiative — at https://www.purdue.edu/president/strategic-initiatives.

Contributor: Daisuke Kihara, professor of Biological Sciences and Computer Science at the Purdue University College of Science

Yuki Kagaya, postdoc Biological Sciences at the Purdue University College of Science

Writer: Cheryl Pierce, Lead Marketing and Public Relations Specialist for the Purdue University College of Science