According to the World Health Organization, each year there are approximately 1 billion cases of influenza, between 3 and 5 million severe cases and up to 650,000 respiratory deaths related to influenza worldwide. Seasonal influenza vaccines must be reformulated each year to match the major circulating strains. When the vaccine matches the predominant strain, it is highly effective; however, when it does not match, it may offer little protection.
The main targets of the influenza 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 from the cell membrane allowing the virus to replicate. Although the properties of the two glycoproteins have been studied previously, 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. 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.”
Rommie Amaro, Principal Investigator of the Project, Emeritus Professor of Chemistry and Biochemistry
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.
This finding 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 an antibody that broadly neutralized -; in other words, not specific to the strain -; and bound to a portion of the protein that appeared 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 looked at the convalescent plasma -; ie plasma from patients recovering from influenza -; they found antibodies specifically targeting the so-called “dark side” of NA under the head. Without seeing the movement of the NA proteins, it was unclear how the antibodies accessed the epitope. Simulations created by Amaro’s lab showed incredible range of motion that provided insight into how the epitope was exposed for antibody binding.
The H1N1 simulation created by the Amaro team contains an enormous amount of detail -; is worth 160 million atoms. A simulation of this size and complexity can only run on a few selected machines around the world. For this work, the Amaro laboratory used Titan at Oak Ridge National Lab, once 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’re mainly interested in HA and NA, but there are other proteins, the M2 ion channel, membrane interactions, glycans, so many other possibilities,” Amaro said. “It also paves the way for other groups to apply similar methods to other viruses. We have modeled SARS-CoV-2 in the past and now H1N1, but there are other flu variants, MERS, RSV, HIV – this is just the start.”
In addition to corresponding author Rommie Amaro, other authors of the article include Lorenzo Casalino and Christian Seitz (both of UC San Diego), Julia Lederhofer and Masaru Kanekiyo (both of the National Allergy Institute and of 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 document.
University of California San Diego
Casalino, L. et al. (2023) Breathing and tilting: mesoscale simulations shed light on influenza glycoprotein vulnerabilities. AEC Core Sciences. doi.org/10.1021/acscentsci.2c00981.