Proteins provide useful targets for medicines to fight a wide variety of diseases. Knowing more about how these complex molecules function might even help scientists fight Covid-19. But that’s not the only reason that fundamental protein research is so interesting to Venkata Mandala PhD ’20.

Mandala’s fascination with proteins began in high school. He had joined a project called Folding@home in which researchers at Stanford University borrowed computational power from hundreds of thousands of volunteers around the world for a cloud-computing project investigating how proteins fold into their three-dimensional structures.

“The question that they were asking—which is still an open question—is whether you can predict what a protein structure will look like based on the string of amino acids that makes it up,” Mandala explains. As he learned more about protein folding and watched protein structures pop up on his computer screen, he was hooked.

What is it about these complex molecules that Mandala finds so captivating? For him, the answer is simple. “Proteins are these tiny, molecular machines that do everything in your body, from holding together muscle cells to making sure your heart beats in a regular fashion to causing diseases. These tasks are all related to protein structure and folding,” he says. As a chemical biologist, Mandala uses physical chemistry techniques to investigate biological questions about the structure and function of proteins, including those essential to influenza viruses and coronaviruses such as Covid-19.

Fighting the flu

Influenza viruses cause influenza (or flu), a common yet potentially serious respiratory infection. Between 2018 and 2019, around 35.5 million people in the United States developed influenza and almost 34,200 died, with most infections caused by one of two strains: influenza A or influenza B. Historically, influenza A has been more common, causing 70% of infections, but in many cases its symptoms can be reduced by the antiviral drugs amantadine and rimantadine. These agents work by blocking M2, a type of protein that sits in the membrane of the virus and plays a key role in viral replication. More recently, however, influenza B has become more prevalent, and the usual antivirals don’t work against it in part because little is known about the structure or function of its analogous M2 protein, Mandala says.

To study M2, Mandala used a technique called solid-state nuclear magnetic resonance (ssNMR) spectroscopy, which was adapted to proteins by his advisor Mei Hong, a professor of chemistry at MIT. “Basically, we have these very strong, superconducting magnets, and we do MRI [magnetic resonance imaging] on proteins instead of humans,” Mandala says. This technique enables him to map the atoms that make up the M2 protein by recording the magnetic signals they give off; as a result, he can visualize the protein’s three-dimensional shape.

Mandala first used ssNMR to examine the more well-characterized influenza A M2 protein (AM2). He discovered that AM2 is a one-way valve that funnels protons in one direction. He then began studying influenza B M2 (BM2), whose structure was basically unknown. He found that BM2 has a similar structure, but BM2 allows proton flow in both directions. “You have this evolutionary trade-off: it’s clear that the viruses evolved to be slightly different,” says Mandala, whose findings were published in February 2020 in Nature Structural & Molecular Biology.

Relevance to Covid-19

Ultimately, Mandala hopes his fundamental scientific research will prove useful to other experts, such as medicinal chemists. “The goal of the project was to get the structure, and then we can say, ‘OK, why doesn’t the drug bind to influenza B?’” Mandala says. “Medicinal chemists can use that information to design drugs.”

The work might even prove useful in addressing the pandemic, as Mandala found when he took his research in an unexpected direction this spring. Realizing that it would be possible to adapt the ssNMR approach to study coronaviruses, he and others in his research group spent six months mapping the structure of an essential envelope protein that conducts ions into SARS-CoV-2, the virus that causes Covid-19. He also established that the drug candidate hexamethylene amiloride binds to the protein, albeit weakly.

“This is the first look at this protein, and we’re excited to share it with the scientific community,” Mandala says. “Now that we know the structure and we have a starting point for the drug, medicinal chemists can iterate on the drug to make it better.”

For Mandala, his research at MIT was an ideal blend of disciplines. “Biology is more hands-on, physics is more theoretical, and biophysical chemistry is a happy middle ground,” he says. “I get to apply this physical chemistry spectroscopic technique to these interesting biological questions.”

Mandala has also appreciated the academic environment at MIT, which he chose because it seemed like the place where he could learn the most. “I really like the energy and the atmosphere. Everyone is super excited about what they do and just wants to work on cool stuff and do science,” he says.

And while Mandala certainly recognizes and appreciates the potential public health application of his work, it is his profound interest in the basic science that keeps him going. “I really enjoy working on new and unknown problems. I always want to learn more, and in science you learn more every single day,” Mandala says. “You do your best to add to the pool of scientific knowledge, and even though my flavor of science is not as applied, it all helps toward our understanding of how the world works.”

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