Computer simulation of H1N1 influenza virus at 160 million atom resolution. Credit: Lorenzo Casalino/Amaro Lab/UC San Diego

Key points:

  • An atomic-level computer model of the H1N1 virus reveals new vulnerabilities, never before seen.
  • The work suggests possible strategies for the design of future vaccines and antivirals against influenza.
  • The research data is openly available, and scientists believe the work could be applied to a myriad of other viruses.

Each year, there are an estimated 1 billion cases of influenza, between 3 to 5 million severe cases and up to 650,000 influenza-related respiratory deaths globally. When the influenza vaccine matches the predominant strain, it is very effective; however, when it does not match, it offers little protection.

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 study, published in ACS Central Science, suggests possible strategies for the design of future vaccines and antivirals against influenza.

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.

Traditionally, flu vaccines have targeted the head of the HA protein based on still images that showed the protein in a tight formation with little movement. But, the UC San Diego team’s model—developed with Oak Ridge’s Titan supercomputer—showed the dynamic nature of the HA protein and revealed a breathing movement that exposed a previously unknown site of immune response, known as an epitope.

This discovery complemented previous work from one of the paper’s co-authors, who had discovered an antibody that was broadly neutralizing. This suggested that the glycoproteins were more dynamic than previously thought, allowing the antibody an opportunity to attach. Simulating the breathing movement of the HA protein established a connection.

Additionally, NA proteins also showed movement at the atomic level with a head-tilting movement. This provided a key insight to co-authors at the National Institute of Allergy and Infectious Diseases. When they looked at convalescent plasma, they found antibodies specifically targeting what is called the “dark side” of NA underneath the head. Without seeing the movement of NA proteins, it wasn’t clear how the antibodies were accessing the epitope. The simulations the UCSD lab created showed an incredible range of motion that gave insight into how the epitope was exposed for antibody binding.

The H1N1 simulation contains an enormous amount of detail—160 million atoms worth. The UCSD team is making the data available to other researchers.

“We’re mainly interested in HA and NA, but there are other proteins, the M2 ion channel, membrane interactions, glycans, so many other possibilities,” said Rommie Amaro, principal investigator on the project. “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 variants, MERS, RSV, HIV — this is just the beginning.”

Information from UCSD.




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