SARS-CoV-2 Spike Protein More Stable, Slower Changing Than Earlier Version

Mahmoud Moradi, University of Arkansas.
Photo Submitted

Mahmoud Moradi, University of Arkansas.

New computational simulations of the behavior of SARS-CoV-1 and SARS-CoV-2 spike proteins prior to fusion with human cell receptors show that SARS-CoV-2, the virus that causes COVID-19, is more stable and slower changing than the earlier version that caused the SARS epidemic in 2003.

Severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) have striking similarities, and researchers do not fully understand why the latter has been more infectious.

The spike proteins of each, which bind to host cell angiotensin converting enzyme 2, otherwise known as the human cell receptor, have been targeted as the potential source of the different transmissibility. Understanding the mechanistic details of the spike proteins prior to binding could lead to the development of better vaccines and medications.

The new finding does not necessarily mean that SARS-CoV-2 is more likely to bind to cell receptors, but it does mean that its spike protein has a better chance of effective binding.

“Once it finds the cell receptor and binds to it, the SARS-CoV-2 spike is more likely to stay bound until the rest of the necessary steps are completed for full attachment to the cell and initiation of cell entry,” said Mahmoud Moradi, associate professor of chemistry and biochemistry in the Fulbright College of Arts and Sciences.

To determine differences in conformational behavior between the two versions of the virus, Moradi’s research team performed an extensive set of equilibrium and nonequilibrium simulations of the molecular dynamics of SARS-CoV-1 and SARS-CoV-2 spike proteins, leading up to binding with cell angiotensin converting enzyme 2. The 3D simulations were done on a microsecond-level, using computational resources provided by the COVID-19 High Performance Computing Consortium.

Equilibrium simulations allow the models to evolve spontaneously on their own time, while nonequilibrium simulations use external manipulation to induce the desired changes in a system. The former is less biased, but the latter is faster and allows for many more simulations to run. Both methodological approaches provided a consistent picture, independently demonstrating the same conclusion that the SARS-CoV-2 spike proteins were more stable.

The models revealed other important findings, namely that the energy barrier associated with activation of SARS-CoV-2 was higher, meaning the binding process happened slowly. Slow activation allows the spike protein to evade human immune response more efficiently, because remaining in an inactive state longer means the virus cannot be attacked by antibodies that target the receptor binding domain.

Researchers understand the importance of the so-called receptor-binding domain, or RBD, which is the critical part of a virus that allows it to dock to human cell receptors and thus gain entry into cells and cause infection. Models produced by Moradi’s team confirm the importance of the receptor-binding domain but also suggest that other domains, such as the N-terminal domain, could play a crucial role in the different binding behavior of SARS-CoV-1 and -2 spike proteins.

N-terminal domain of a protein is a domain located at the N-terminus or simply the start of the polypeptide chain, as opposed to the C-terminus, which is the end of the chain. Though it is near the receptor-binding domain and is known to be targeted by some antibodies, function of the N-terminal domain in SARS-CoV-1 and -2 spike proteins is not completely understood. Moradi’s team is the first to find evidence for potential interaction of the N-terminal domain and the receptor binding domain.

“Our study sheds light on the conformational dynamics of the SARS-CoV-1 and SARS-CoV-2 spike proteins,” Moradi said. “Differences in the dynamic behavior of these spike proteins almost certainly contribute to differences in transmissibility and infectivity.”

The researchers’ study, “Prefusion Spike Protein Conformational Changes Are Slower in SARS-CoV-2 than SARS-Cov-1,” was published in Journal of Biological Chemistry.

About the University of Arkansas: As Arkansas' flagship institution, the U of A provides an internationally competitive education in more than 200 academic programs. Founded in 1871, the U of A contributes more than $2.2 billion to Arkansas’ economy through the teaching of new knowledge and skills, entrepreneurship and job development, discovery through research and creative activity while also providing training for professional disciplines. The Carnegie Foundation classifies the U of A among the few U.S. colleges and universities with the highest level of research activity. U.S. News & World Report ranks the U of A among the top public universities in the nation. See how the U of A works to build a better world at Arkansas Research News.


Mahmoud Moradi, associate professor, chemistry and biochemistry
J. William Fulbright College of Arts and Sciences

Matt McGowan, science and research communications officer
University Relations


Muhammad Ali Muhammad Selected as September Student Leader of the Month

Muhammad Ali Muhammad, a junior originally from Islamabad, Pakistan, who is studying poultry science, has been selected as the Student Leader of the Month for September 2022.

Speed Limits Reduced to 20 mph in Campus, Residential Areas

The U of A has lowered the default speed limit through the campus area from 25 mph to 20 mph as part of a collaborative effort with the City of Fayetteville.

Engineering Faculty Travel to Monterrey, Mexico, to Connect with Educators

Burak Eksioglu and Alan Vazquez, professors in the Department of Industrial Engineering, recently traveled to Monterrey, Mexico, as part of an effort to recruit graduate students and build relationships.

WISE Symposium Honors Supply Chain Legends and Looks to the Future

The symposium kicks off Oct. 6-7 at the Sam M. Walton College of Business and will highlight female supply chain management pioneers.

University of Arkansas Latin American Ensemble to Perform at U of A Fort Smith

The University of Arkansas Latin American Ensemble will give a special performance at UA Fort Smith at 6:30 p.m. today, Monday, Oct. 3, in the Campus Center Reynolds Room.

News Daily