The dynamic movement of H1N1 proteins exposes previously unknown vulnerabilities.
The World Health Organization reports that there are approximately 1 billion cases of influenza per year, with 3 to 5 million severe cases and up to 650,000 influenza-related respiratory deaths worldwide. To be effective, seasonal flu vaccines must be updated annually to align with the predominant strains of the virus. When the vaccine matches the prevalent strain, it provides substantial protection. However, if the vaccine and virus strains do not match, the vaccine may provide limited defense.
The glycoproteins hemagglutinin (HA) and neuraminidase (NA) are the main targets of the influenza vaccine. The HA protein facilitates attachment of the virus to host cells, while the NA protein acts like a scissor to detach the HA from the cell membrane, allowing the virus to multiply. Despite previous studies on the properties of these glycoproteins, a complete understanding of their movement does not exist.
For the first time, researchers at the University of California, San Diego have created an atomic-level computer model of the H1N1 virus that reveals new vulnerabilities through the “breathing” and “tilting” movements of glycoproteins. This book, published in AEC Core Sciencessuggests possible strategies for the design of future influenza vaccines and antivirals.
“When we first saw how dynamic these glycoproteins were, the high degree of respiration and tilt, we actually wondered if there was something wrong with our simulations,” said Emeritus Professor of Chemistry and Biochemistry Rommie Amaro, who is the project’s principal investigator. . “Once we knew our models were correct, we realized the enormous potential of this discovery. This research could be used to develop methods to keep the protein locked open so that it is constantly accessible to antibodies.
Traditionally, flu vaccines targeted the head of the HA protein based on still images that showed the protein in a tight formation with little movement. Amaro’s model showed the dynamic nature of the HA protein and revealed a respiratory movement that exposed a previously unknown immune response site known as an epitope.
Computer model of the H1N1 flu virus – 160 million atom detail. Credit: University of California – San Diego
This discovery complemented previous work by one of the paper’s co-authors, Ian A. Wilson, Hansen Professor of Structural Biology at the Scripps Research Institute, who had discovered a broadly neutralizing antibody – in other words, not strain-specific – and bound to a part of the protein that seemed unexposed. This suggested that the glycoproteins were more dynamic than previously thought, allowing the antibody to attach. The simulation of the respiratory movement of the HA protein made a connection.
NA proteins also showed atomic-level motion with head-tilting motion. This provided key insight to co-authors Julia Lederhofer and Masaru Kanekiyo of the National Institute of Allergy and Infectious Diseases. When they watched the convalescents
Amaro is making the data available to other researchers who can discover even more about how the flu virus moves, grows and evolves. “We are mainly interested in HA and NA, but there are other proteins, the M2 ion channel, membrane interactions, glycans and so many other possibilities,” Amaro said. “It also paves the way for other groups to apply similar methods to other viruses. We modeled