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Artificial intelligence reveals a never-before described 3D structure in rotavirus spike protein

Of the three groups of rotavirus that cause gastroenteritis in people, called groups A, B and C, groups A and C affect mostly children and are the best characterized. On the other hand, of group B, which causes severe diarrhea predominantly in adults, little is known about the tip of the virus’s spike protein, called VP8* domain, which mediates the infection of cells in the gut.

“Determining the structure of VP8* in group B rotavirus is important because it will help us understand how the virus infects gastrointestinal cells and design strategies to prevent and treat this infection that causes severe diarrheal outbreaks,” said corresponding author Dr B. V. Venkataram Prasad, professor of biochemistry and molecular biology at Baylor College of Medicine.

The team’s first step was to determine the 3D structure of VP8* B using X-Ray crystallography, a laborious and time-consuming process. However, this traditional approach was unsuccessful in this case. The researchers then turned to a recently developed artificial intelligence-based computational program called AlphaFold2.

“AlphaFold2 predicts the 3D structure of proteins according to their genetic sequence,” said first author and co-corresponding author Dr. Liya Hu, assistant professor of biochemistry and molecular biology at Baylor. “We knew that the protein sequence of VP8* of rotavirus group B was about 10% similar to the sequences of VP8* of rotavirus A and C, so we expected differences in the 3D structure as well. But we were surprised when AlphaFold2 predicted a 3D structure for the VP8* B that was not just totally different from that of the VP8* domain in rotavirus A and C, but also that no other protein before had been reported to have this structure.”

With this information in hand, the researchers went back to the lab bench and experimentally confirmed that the structure of VP8* B predicted by ALphaFold2 indeed coincided with the actual structure of the protein using X-ray crystallography.

How rotavirus infects cells

Previous research has shown that rotavirus A and C infect cells by using the VP8* domain to bind to specific sugar components on histo-blood group antigens, including the A, B, AB and O blood groups, present in many cells in the body. It has been proposed that the ability of different rotavirus to bind to different sugars on the histo-group antigens might explain why some of these viruses specifically infect young children while others affect other populations. Unlike the VP8* A and VP8* C, the sugar specificity of VP8* B had not been characterized until now.

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