According to the World Health Organization, there are an estimated 1 billion cases of flu each year, between 3 and 5 million severe cases, and up to 650,000 flu-related respiratory deaths worldwide. Seasonal flu vaccines must be reformulated each year to match the predominately circulating strains. When the vaccine matches the predominant strain, it is highly effective; however, if it doesn’t match, it may offer little protection.
The main targets of the flu vaccine are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). While the HA protein helps the virus bind to the host cell, the NA protein acts like scissors to cut the HA away from the cell membrane, allowing the virus to replicate. Although the properties of both glycoproteins have been studied before, 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 glycoprotein “breathing” and “tilting” movements. This work, published in ACS Central Sciencesuggests possible strategies for the design of future flu vaccines and antivirals.
When we first saw how dynamic these glycoproteins were, the great amount of breathing and tilting, we actually wondered if there was something wrong with our simulations. 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 open so that it is constantly accessible to antibodies.”
Rommie Amaro, principal investigator of the project, Distinguished Professor of Chemistry and Biochemistry
Traditionally, flu vaccines have focused on 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, revealing a breathing movement that exposed a previously unknown site of immune response known as an epitope.
This discovery added to 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 an antibody that was largely neutralizing -; in other words, not tribe-specific -; and bound to a portion of the protein that appeared unexposed. This suggested that the glycoproteins were more dynamic than previously thought, giving the antibody a chance to attach. By simulating the breathing movement of the HA protein, a connection was made.
NA proteins also showed movement at the atomic level with a head-tilting motion. This provided an important insight for co-authors Julia Lederhofer and Masaru Kanekiyo of the National Institute of Allergy and Infectious Diseases. When they looked at convalescent plasma -; ie plasma from patients recovering from the flu -; they found antibodies specifically targeting what is called the “dark side” of NA under the head. Without seeing the movement of NA proteins, it was not clear how the antibodies gained access to the epitope. The simulations Amaro’s lab made showed an incredible range of motion that provided insight into how the epitope was exposed to antibody binding.
The H1N1 simulation that Amaro’s team created has a ton of detail -; Worth 160 million atoms. A simulation of this size and complexity can only be performed on a select few machines in the world. The Amaro lab was used for this work Titan at Oak Ridge National Lab, formerly one of the largest and fastest computers in the world.
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 particularly interested in HA and NA, but there are other proteins, the M2 ion channel, membrane interactions, glycans, so many other possibilities,” said Amaro. “This also paves the way for other groups to apply similar methods to other viruses. We’ve modeled SARS-CoV-2 in the past and now H1N1, but there are other flu strains, MERS, RSV, HIV – this is just the beginning.”
In addition to corresponding author Rommie Amaro, other authors on the paper include Lorenzo Casalino and Christian Seitz (both UC San Diego), Julia Lederhofer and Masaru Kanekiyo (both National Institute of Allergy and Infectious Diseases/NIH), Yaroslav Tsybovsky (Frederick National Laboratory for cancer research) and Ian A. Wilson (The Scripps Research Institute).
Funding was provided in part by the National Institutes of Health (T32EB009380), the National Science Foundation Graduate Research Fellowship (DGE-1650112), the Department of Energy (INCITE BIP160), and the National Science Foundation (OAC-1811685). A full list of funding sources can be found in the newspaper.
University of California San Diego
Casalino, L., et al. (2023) Breathing and Tilting: Mesoscale Simulations Illuminate Influenza Glycoprotein Vulnerabilities. ACS Central Science. doi.org/10.1021/acscentsci.2c00981.