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The Doorway into COVID-19

Published on May 21, 2020 by Faith Singer-Villalobos

With confirmed cases worldwide surpassing 4.4 million and continuing to grow, scientists are pushing forward with efforts to develop vaccines and treatments to slow the COVID-19 pandemic and lessen the disease's damage.

But before a vaccine can be developed, scientists need to fully understand the viral envelope, the outermost layer of the virus, which protects its genetic material when traveling between host cells. The envelopes are typically derived from important proteins on the host cell membrane. The proteins can help the virus avoid the host immune system, but also serve to identify and bind to receptor sites, allowing the virus to enter and infect the host—us.

"If you're studying the structure of the virus, the spike protein (S-protein) is the most important part of COVID-19," said Lin Li, an assistant professor in Computational Biophysics at the Physics Department and Border Biomedical Research Center of The University of Texas at El Paso.

Lin Li, Assistant Professor, Computational Biophysics, Border Biomedical Research Center of The University of Texas at El Paso

Li and his colleagues use physics-based approaches and computational tools to study biological problems that are important to human health. Since January 2020, the entire team has been focused on COVID-19.

The S-protein protrudes from the surface of the viral envelope giving the virus its "crown" appearance, a common feature across the coronavirus family, including SARS-CoV-1 and COVID-19 (also known as SARS-CoV-2). The S-protein performs two primary tasks that aid in host infection. It mediates the attachment between the virus and host cell surface receptors, and it facilitates viral entry into the host cell by assisting in the fusion of the viral and host cell membranes.

Another important protein involved in COVID-19 infection is ACE2 (Angiotensin-converting enzyme 2). ACE2 is attached to the outer surface of cells in the lungs, arteries, heart, kidney, and intestines. It serves as the entry point into cells. During infection, ACE2 binds to the receptor of the S-protein.

"Imagine that the S-protein is a hand and the ACE2 protein is like a door—both proteins must interact if this virus wants to open the door into the human cell. If there's no interaction, the virus can't enter the human cell," Li said. "We want to understand the physics, and the ‘how' and ‘why', behind this crucial interaction to model how the virus interacts with the host."

The structure of the virus indicates its function. If the researchers have a full understanding of the function, this knowledge could help scientists test different drugs that are critical to the development of coronavirus vaccines and therapeutics.

"To enable our research, we used supercomputers to simulate the binding and physics features of the S-protein and ACE2 interacting, and during this process we identified some key residues," Li said. A residue is a specific amino acid at a specific location within the polymeric chain of a protein. Which residues on COVID-19 make the binding between the S-protein and ACES2 so strong? "Our focus is to find out," Li said.

As one of the leading academic supercomputing centers in the world, the Texas Advanced Computing Center (TACC) is providing Li's group with computing resources that make their work more efficient and helps lay the path for scientific results.

"If we want to explain the ‘how' and ‘why,' then supercomputers are very helpful because they can do simulations with high resolution in time, length, and size," Li said. He compares experiments to determine the structure of the virus to taking pictures with a camera. Supercomputer simulations move the process several steps further, connecting the pictures into movies, allowing researchers to review the whole mechanism.

Yixin Xie, the team leader of this project in Li's group said, "We've been using TACC's Stampede2 and Lonestar5 supercomputers. Lonestar5 has helped us significantly because the types of simulations we're doing requires faster performance, and GPUs are much faster than CPUs." For applications that can use them effectively, GPUs (graphical processing units) run some scientific calculations much faster than a CPU (central processing unit) approach.

This figure shows the structure of the COVID-19 S-protein binding to the human ACE2 enzyme. The magenta color represents ACE2; the other areas are the "spike" protein of the virus. Each spike is composed of three protein monomers shown in blue, green, and orange. The surface shows the overall structure, while the detailed structures are shown inside the surface with solid colors. [Credit: Lin Li's Lab at UT El Paso]

John Fonner, a research associate in TACC's Life Sciences Computing group, said TACC is entrusted to build and deploy supercomputers for open science use. "We want to take the resources we have and enable researchers to make discoveries that transform the world. We want to do this with COVID-19."

Using molecular dynamics simulations on TACC's systems, Li was able to simulate the process of the S-protein binding to the ACE2 protein, giving a glimpse into how and why they bind together, and allowing the researchers to compare SARS-CoV-1 and COVID-19.

SARS-CoV-1, called the first pandemic of the 21st century, infected 8,098 people in 26 countries and killed 774.

"SARS-1 and COVID-19 have similar sequences and structures, however, the binding mechanisms are slightly different," Li said. "For example, we found on COVID-19 there are about 20 important amino acid residues interacting with ACE2, and we're trying to identify the roles of those key amino acids. Some of the amino acid residues that interact with ACE2 are very strong and others are very weak. We're trying to identify the top 5 or top 10 amino acids, and want to see if we can use something to block them. There are mutations that occur on key locations of these residues. This makes COVID-19 more dangerous because it infects human cells faster and in greater amounts than SARS-1."

Another finding made by Li and his team is what they call the "flip." Usually the S-protein interface domain is hidden inside the protein, but their research found that something triggers the interface domain to release and flip outward allowing it to interact with human cells. To use Li's analogy, the interface domain acts as the hand, which is hidden because the arm is bent. To open the door of the human cell, the arm needs to reach out so the hand can open the door. This is a new finding that will serve as the next step in the group's research.

When Li decided to become a scientist, he wanted to work on the most important problems.

"For me, biology problems related to health are the most important in the world. COVID-19 will be defeated, but what about future viruses, such as SARS3 or SARS4? We need to learn as much as possible from COVID-19 so we can be well-prepared in the future. Our work is more fundamental—we hope our research informs our understanding of the entire family of coronaviruses that infect humans."

Story Highlights

Lin Li and his colleagues at UT El Paso use physics-based approaches and computational tools to study biological problems that are important to human health. Since January 2020, the entire team has been focused on COVID-19.

Currently, the focus of their study involves the crucial interaction of the S-protein and ACE2—both proteins must interact for the virus to infect the human cell.

TACC supercomputers (Stampede2, Lonestar5) enable their research by allowing Li's team to perform simulations with high resolution in time, length, and size.

This knowledge will help scientists test different drugs that are critical to the development of coronavirus vaccines and therapeutics now and for future viruses.


Faith Singer-Villalobos

Communications Manager | 512-232-5771

Aaron Dubrow

Science And Technology Writer

Jorge Salazar

Technical Writer/Editor | 512-475-9411