New computer 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 outbreak in 2003.
The severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) have striking similarities, and researchers don’t fully understand why the latter was more infectious.
Each’s spike proteins, which bind to the host cell’s angiotensin-converting enzyme 2, otherwise known as the human cell receptor, have been targeted as a potential source of the differential transmissibility. Understanding the mechanistic details of spike proteins before binding might lead to the development of better vaccines and drugs.
The new finding doesn’t 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 binding effectively.
“Once it has found the cellular receptor and bound to it, the SARS-CoV-2 spike is more likely to stay bound until the rest of the necessary steps are complete for complete attachment to the cell. and initiation of cell entry,” said Mahmoud Moradi. , associate professor of chemistry and biochemistry at 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 a comprehensive set of equilibrium and non-equilibrium simulations of the molecular dynamics of the SARS-CoV-1 spike proteins and SARS-CoV-2, leading to binding with cellular angiotensin converting enzyme 2. 3D simulations were performed at the microsecond level, using computing resources provided by the COVID-19 High Performance Computing Consortium .
Equilibrium simulations allow models to evolve spontaneously on their own time, while out-of-equilibrium simulations use external manipulation to induce desired changes in a system. The former is less biased, but the latter is faster and can run many more simulations. Both methodological approaches provided a consistent picture, independently demonstrating the same conclusion that SARS-CoV-2 spike proteins were more stable.
The models revealed other important findings, namely that the energy barrier associated with SARS-CoV-2 activation was higher, meaning that the binding process occurred slowly. Slow activation allows the spike protein to evade the human immune response more effectively, because staying longer in an inactive state 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 with receptors on human cells and thus enter cells and cause an infection. The 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, might play a crucial role in the different binding behavior of proteins from spike SARS-CoV-1 and -2.
The N-terminal domain of a protein is a domain located at the N-terminus or just the beginning of the polypeptide chain, as opposed to the C-terminus, which is the end of the chain. Although it is close to the receptor binding domain and is known to be targeted by some antibodies, the function of the N-terminal domain in the SARS-CoV-1 and -2 spike proteins is not completely clear. understood. Moradi’s team is the first to find evidence for a potential interaction of the N-terminal domain and the receptor binding domain.
“Our study sheds light on the conformational dynamics of 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, “Conformational changes of the Prefusion Spike protein are slower in SARS-CoV-2 than in SARS-Cov-1,” was published in Journal of Biological Chemistry.
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Materials provided by University of Arkansas. Original written by Matt McGowan. Note: Content may be edited for style and length.
