H1N1 influenza virus simulation at 160 million atom resolution. Credit: Lorenzo Casalino / Amaro Lab / UC San Diego
Seasonal flu vaccinations must be updated each year to match the predominant strain of influenza. However, if the vaccine and virus strains are not a match, the vaccine may offer limited protection.
The flu vaccination uses the hemagglutinin (HA) and neuraminidase (NA) glycoproteins as primary targets. The HA protein facilitates the virus's attachment to host cells, while the NA protein acts as a scissor to detach the HA from the cell membrane, enabling the virus to multiply.
Researchers at the University of California San Diego have created an atomic-level computer model of the H1N1 virus that reveals new vulnerabilities via glycoprotein "breathing" and "tilting" movements. This article, published in ACS Central Science, suggests future vaccinations and antivirals against influenza.
"We actually wondered if there was something wrong with our simulations," said Distinguished Professor of Chemistry and Biochemistry Rommie Amaro, who is the principal investigator on the research. "This discovery could be utilized to develop methods for keeping the protein locked open so that antibodies may always find it."
Vaccines against flu have traditionally focused on the HA protein in still images that showed it in a tight formation with little movement. Amaro's model revealed a breathing sensation that revealed a previously unknown immune response, known as an epitope.
160 million atoms of detail in a computer model of the H1N1 influenza virus. Credit: University of California – San Diego
Ian A. Wilson, a fellow author of the paper, had discovered an antibody that was broadly neutralizing — in other words, not strain-specific — and bound to a portion of the protein that was unexposed. This suggested that the glycoproteins were more dynamic than previously assumed, allowing the antibody to attach.
NA proteins also showed a head tilting movement, according to Julia Lederhofer and Masaru Kanekiyo of the National Institute of Allergy and Infectious Diseases. When they examined convalescent plasma, they discovered antibodies that specifically targeted what is called the "dark side" of NA underneath the head. It wasn't clear how the antibodies accessed the epitope.
The H1N1 simulation Amaro's team created is massive in detail — 160 million atoms worth. A simulation of this size and complexity can only be performed on a few select machines in the world. Titan at Oak Ridge National Lab was used for this study.
Amaro is releasing the data to other researchers who may benefit from it further by examining other viruses such as SARS-CoV-2 and now H1N1, as well as other influenza strains.
Lorenzo Casalino, Christian Seitz, Yaroslav Tsybovsky, Ian A. Wilson, Masaru Kanekiyo, and Rommie E. Amaro, ACS Central Science, DOI: 10.1021/acscentsci.2c00981
The National Institutes of Health, the National Science Foundation, the US Department of Energy, and the National Science Foundation have all contributed to the study.
