The HA protein facilitates the viruss attachment to host cells, while the NA protein acts as a scissor to remove the HA from the cell membrane, allowing the virus to increase. Replicating the breathing movement of the HA protein established a connection.
NA proteins also showed movement at the atomic level with a head-tilting motion. Amaro is making the information offered to other researchers who can uncover even more about how the influenza virus moves, grows, and progresses. “Were primarily interested in HA and NA, but there are other proteins, the M2 ion channel, membrane interactions, glycans, and so lots of other possibilities,” Amaro specified.
Computer system simulation of H1N1 influenza infection at 160 million atom resolution. Credit: Lorenzo Casalino/ Amaro Lab/ UC San Diego
The vibrant movement of H1N1 proteins exposes formerly unknown vulnerabilities.
To be effective, seasonal flu vaccines must be updated each year to align with the primary stress of the infection. If the vaccine and virus pressures are not a match, the vaccine may supply limited defense.
The hemagglutinin (HA) and neuraminidase (NA) glycoproteins are the main targets of the flu vaccine. The HA protein facilitates the viruss attachment to host cells, while the NA protein acts as a scissor to detach the HA from the cell membrane, enabling the infection to increase. Despite previous research studies on the properties of these glycoproteins, a complete understanding of their movement does not exist.
For the first time, scientists at the University of California San Diego have actually developed an atomic-level computer design of the H1N1 virus that exposes new vulnerabilities through glycoprotein “breathing” and “tilting” movements. This work, published in ACS Central Science, recommends possible techniques for the design of future vaccines and antivirals versus influenza.
” When we initially saw how vibrant these glycoproteins were, the large degree of breathing and tilting, we in fact wondered if there was something incorrect with our simulations,” stated Distinguished Professor of Chemistry and Biochemistry Rommie Amaro, who is the principal investigator on the job. “Once we knew our designs were correct, we recognized the enormous capacity this discovery held. This research study could be used to establish approaches of keeping the protein locked open so that it would be continuously available to antibodies.”
Generally, influenza vaccines have targeted the head of the HA protein based upon still images that showed the protein in a tight formation with little motion. Amaros design revealed the dynamic nature of the HA protein and revealed a breathing motion that exposed a previously unidentified website of immune response, known as an epitope.
Computer system design of H1N1 influenza infection– 160 million atoms of detail. Credit: University of California– San Diego
This discovery matched previous work from one of the papers co-authors, Ian A. Wilson, Hansen Professor of Structural Biology at The Scripps Research Institute, who had found an antibody that was broadly neutralizing– to put it simply, not strain-specific– and bound to a part of the protein that appeared unexposed. This suggested that the glycoproteins were more dynamic than formerly believed, allowing the antibody a chance to attach. Replicating the breathing movement of the HA protein established a connection.
NA proteins also revealed motion at the atomic level with a head-tilting motion. Without seeing the movement of NA proteins, it wasnt clear how the antibodies were accessing the epitope.
The H1N1 simulation Amaros group developed includes a massive amount of detail– 160 million atoms worth. A simulation of this size and complexity can only operate on a few choose devices on the planet. For this work, the Amaro lab used Titan at Oak Ridge National Lab, formerly among the largest and fastest computer systems in the world.
Amaro is making the information offered to other scientists who can discover even more about how the influenza infection moves, grows, and progresses. “Were primarily thinking about HA and NA, however there are other proteins, the M2 ion channel, membrane interactions, glycans, therefore lots of other possibilities,” Amaro stated. “This likewise leads the way for other groups to use comparable approaches to other infections. Weve designed SARS-CoV-2 in the past and now H1N1, but there are other influenza variations, MERS, RSV, HIV– this is simply the beginning.”
Reference: “Breathing and Tilting: Mesoscale Simulations Illuminate Influenza Glycoprotein Vulnerabilities” by Lorenzo Casalino, Christian Seitz, Julia Lederhofer, Yaroslav Tsybovsky, Ian A. Wilson, Masaru Kanekiyo and Rommie E. Amaro, 8 December 2022, ACS Central Science.DOI: 10.1021/ acscentsci.2 c00981.
The research study was moneyed by the National Institutes of Health, the National Science Foundation, the US Department of Energy, and the National Science Foundation.
