Computational methods reveal 3D structures of viral proteins

These rapid changes mean that researchers are still trying to understand a variety of viral proteins and how exactly they increase the infectivity of viruses. This knowledge could be crucial for developing new or better treatments to fight viruses.

Now a team of scientists from the Gladstone Institutes and the Innovative Genomics Institute, led by Dr. Jennifer Doudna, has used computational tools to predict the three-dimensional shapes of nearly 70,000 viral proteins.

The researchers matched the 3D shapes to the structures of proteins whose functions are already known. Since the structure of a protein directly contributes to its biological function, their study provides new insights into what exactly these lesser-known proteins do.

Their further findings, which they published in the journal NatureThe researchers discovered a powerful way that viruses evade the immune system. In fact, they found that viruses that infect bacteria and those that infect higher organisms – including humans – have a similar, ancient mechanism for evading the host's immune defenses.

As viruses with pandemic potential emerge, it is important to understand how they interact with human cells. Our new study provides a tool to predict what these emerging viruses can do.”

Jennifer Doudna, PhD, Professor, University of California, Berkeley

Sequence versus form

To figure out the function of a protein, researchers typically look for similarities between its particular sequence of amino acid “building blocks” and the amino acid sequences of other proteins with known functions. But because viruses evolve so quickly, many viral proteins don't bear much resemblance to known proteins.

But just as different combinations of building blocks can create very similar structures, proteins with different sequences can also share common three-dimensional shapes and play similar biological roles.

“We looked at similarities between protein shapes as a promising alternative for determining the function of viral proteins,” says Dr. Jason Nomburg, a postdoctoral fellow in Doudna's lab at Gladstone and first author of the study. “We asked ourselves: What can we learn from protein structures that we might miss by looking only at the sequences?”

To answer this question, the team turned to an open-access research platform called AlphaFold, which predicts the 3D shape of a protein based on its amino acid sequence. They used AlphaFold to predict the shapes of 67,715 proteins from nearly 4,500 species of viruses that infect eukaryotes (organisms such as plants, animals, and humans that contain DNA in their cell nuclei). They then used a deep learning tool to compare the predicted structures to those of known proteins from other viruses, as well as non-viral proteins from eukaryotes.

“This would not have been possible without recent advances in these types of computational tools that allow us to accurately and quickly predict and compare protein structures,” says Nomburg.

Unexpected connections

The team found that 38 percent of the newly predicted protein shapes matched already known proteins and found important connections between them.

For example, some of the newly predicted structures belong to the group of so-called “UL43-like proteins” found in human herpes viruses, which include those that cause mononucleosis and chickenpox.

“These new viral proteins look frighteningly similar to known non-viral proteins in mammalian cells that help transport the building blocks of DNA and RNA across membranes,” says Nomburg. “Before this work, we didn't know that these proteins could act as transporters.”

The team also found similarities between the newly predicted viral protein structures and the structures of other viral proteins. Most notably, the analysis revealed a strategy for evading host immune defenses that is common both in viruses that infect animals and in viruses called phages that infect bacteria. This mechanism appears to have been conserved throughout evolution.

“This is a very exciting area because there is increasing evidence that the innate immunity of complex organisms, including humans, resembles many different types of innate immunity in bacteria,” says Nomburg. “We will study these evolutionary connections in more detail because a better understanding of the way our cells respond to viruses could lead to new approaches to improving antiviral defenses.”

The team has now made the 70,000 newly predicted viral protein structures, as well as the data from their new analyses, publicly available. These resources could provide other researchers with the opportunity to discover additional structural connections between proteins that will deepen knowledge of how viruses interact with their hosts.

“From a disease control perspective, this work is exciting because it opens up new potential avenues for developing broadly effective antiviral therapies,” says Doudna. “For example, if we can find common, conserved ways that viruses evade immunity, this could lead to potent antivirals that are effective against many different viruses simultaneously.”