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An international research team led by a Korean scientist has succeeded in designing large-scale protein structures that faithfully replicate the self-assembly principles found in naturally occurring viruses, using artificial intelligence (AI).
Protein nanocages are emerging as highly promising materials in the biomedical field for next-generation drug delivery. These structures are hollow, nanometer-scale, and form spontaneously through the binding of multiple proteins. Their interior space allows them to stably carry drugs, genetic materials, and enzymes, while antigens can be attached to their outer surface. However, previous design methods primarily relied on computationally derived "perfect symmetric structures," which significantly restricted the size and complexity of structures that could be created from a single protein building block.
Natural viruses utilize a single protein type, repeated hundreds to thousands of times, to construct massive shells by subtly adjusting each protein's position and local environment. This principle, known as quasisymmetry, has now been successfully implemented in the design of artificial proteins by the research team. They identified that the key to expanding viral shell size lies in controlling the angles and curvature between protein building blocks. An overly flat arrangement prevents shell closure, while excessive curvature results in a structure that is too small. By precisely engineering this balance, the team enabled a single protein to occupy both pentagonal and hexagonal environments simultaneously, depending on its position within the assembly. They achieved this by using a trimeric unit (a cluster of three proteins) as the fundamental building block and leveraging RFdiffusion, an AI-based tool, to design novel connecting structures. This approach, similar to stacking interlocking blocks at various angles, allowed the proteins to fit together in diverse orientations, leading to the formation of a large dome-shaped shell instead of a flat sheet.
The research team successfully produced the artificially designed proteins using E. coli and subsequently examined their morphology using advanced cryo-electron microscopy. The experimental results confirmed that these proteins spontaneously self-assembled into spherical shells, with sizes ranging significantly from a minimum of 70 nm to a maximum of 220 nm. The smallest structures observed adopted the form of intricate "nano-soccer balls," while the largest structures were more than three times that size, demonstrating the successful formation of various large-scale protein assemblies.
This study has garnered considerable scientific attention due to its innovative approach: designing large virus-like structures using a single, entirely AI-created artificial protein, rather than repurposing existing viral proteins. If commercialized, this technology is poised to revolutionize the biomedical sector, offering transformative applications such as advanced targeted drug and genetic material delivery systems, and innovative vaccine antigen presentation platforms. Future research endeavors are planned to achieve more precise and uniform size control of these structures by using internal scaffold proteins or nucleic acids as templates. Additionally, a related study on artificial protein structures, spearheaded by Prof. Baker with Prof. Sangmin Lee as a co-author, was published concurrently in Nature, highlighting Prof. Lee’s rare achievement of being the corresponding author on one paper and co-author on another in the world's leading scientific journal.
Prof. Sangmin Lee of POSTECH commented that "Viruses are the finest example in nature showing that perfect symmetry is not the only path to sophisticated molecular architecture." He further elaborated that this study demonstrates how precise control over the local geometry of protein blocks can fine-tune the size and shape of the final assembly, much like subtle changes in the angle between molecular tiles can transform a flat plane into a massive dome. Sung-Soo Kim, Director General for R&D Policy at MSIT, lauded this achievement as a remarkable display of world-class fundamental research capability by a leading Korean scientist, accomplished through collaboration with a Nobel laureate. He affirmed MSIT's commitment to providing continuous support to enhance the research capacity of Korean scientists and foster globally pioneering results.