New Insights into Protein Folding Differences Between SARS-CoV-1 and SARS-CoV-2

Medical News: A team of international researchers has shed new light on the behavior of proteins that play a key role in the interaction between SARS-CoV-1 and SARS-CoV-2 and human cells. Their findings may help explain why SARS-CoV-2, the virus responsible for COVID-19, spreads more easily than SARS-CoV-1. By studying the folding pathways of these viruses' receptor binding domains (RBD), the team identified unique differences between the two viruses. This Medical News article highlights how forces impact the refolding process of proteins in these viruses, which has broad implications for our understanding of viral transmission and infection rates.


New Insights into Protein Folding Differences Between SARS-CoV-1 and SARS-CoV-2

Researchers involved in this study came from the Institute for Computational Sciences and Technology, Ho Chi Minh City, Vietnam; Pennsylvania State University, USA; and the Institute of Physics, Polish Academy of Sciences, Poland.
 
Why Protein Folding Matters
Proteins, the building blocks of life, must fold into specific shapes to function properly. In the case of viruses, protein folding is crucial for their ability to infect host cells. Misfolded proteins can lead to malfunctions and diseases. Studying how proteins fold - especially under force - provides insights into how viral proteins behave under the stress of infection. For example, understanding how the receptor binding domain (RBD) of the spike protein folds can explain why SARS-CoV-2 is more infectious than SARS-CoV-1.
 
The RBDs of SARS-CoV-1 and SARS-CoV-2 play a key role in how these viruses bind to the human angiotensin-converting enzyme 2 (ACE2) receptor, a protein on the surface of human cells. The better the fit between the RBD and ACE2, the easier it is for the virus to infect cells.
 
The Role of Forces in Protein Folding
The research team used simulations to explore how external forces affect the folding process of these viral RBDs. When a small pulling force is applied to a protein, it can slow down or even disrupt the folding process. This is similar to how proteins behave in real-world situations, such as when they interact with other molecules in the body. By mimicking this environment, the researchers were able to uncover key differences in how the two viruses' proteins fold.

In their study, the team applied a force of 5 piconewtons (pN) to the proteins’ termini during the folding process. Surprisingly, while the folding time of SARS-CoV-2 RBD increased significantly under force, SARS-CoV-1’s RBD was largely unaffected.
 
Key Findings from the Study
The study revealed several important insights:
-SARS-CoV-2 is more sensitive to external force: When a force was applied, SARS-CoV-2 RBD took much longer to fold. The number of successful folding events dropped dramatically, indicating that force slows down SARS-CoV-2 RBD’s ability to refold. The folding time of SARS-CoV-2 RBD under force was over 5,600 n anoseconds (ns), compared to just 257 ns without force.
 
-SARS-CoV-1 is less sensitive to force: In contrast, SARS-CoV-1 RBD showed minimal changes in folding time when subjected to the same force. The folding time remained relatively stable, suggesting that the older virus’s RBD is more resistant to external stress during folding.
 
-Misfolded states are common but behave differently: Both SARS-CoV-1 and SARS-CoV-2 can form misfolded intermediate states during the folding process. These states involve non-native entanglements - parts of the protein that fold incorrectly. However, SARS-CoV-1 proteins are better at avoiding these misfolded states when force is applied, likely due to how the force influences the protein’s structure.
 
-SARS-CoV-2 has a unique vulnerability: The team’s analysis suggested that the misfolded states of SARS-CoV-2 are more likely to be kinetically trapped. This means that once SARS-CoV-2 proteins misfold, they struggle to correct themselves, which could affect how the virus behaves under stress.
 
-Pulling forces prevent misfolding in SARS-CoV-1: Interestingly, the external force applied to SARS-CoV-1’s RBD appears to prevent misfolding by guiding the protein towards a more stable folding pathway. In contrast, SARS-CoV-2 does not benefit from the force in the same way, as the applied force seems to create additional folding barriers that trap the protein in misfolded states.
 
What This Means for Understanding Viral Behavior
The differences in how SARS-CoV-1 and SARS-CoV-2 RBDs respond to force may help explain why SARS-CoV-2 spreads more easily. The fact that SARS-CoV-2’s RBD is more sensitive to stress could mean that under certain conditions, such as when the immune system is attacking the virus, its proteins might misfold and become less functional.
 
The study also suggests that external forces could play a role in viral evolution. Over time, viruses like SARS-CoV-2 might evolve proteins that are less sensitive to stress, allowing them to infect hosts more efficiently. Understanding these folding mechanisms could provide clues for future therapeutic approaches.
 
Why Is SARS-CoV-2 So Effective?
While both SARS-CoV-1 and SARS-CoV-2 share around 80% of their genetic sequence, their RBDs interact with human cells in very different ways. SARS-CoV-2 binds more effectively to the ACE2 receptor, which is one reason it spreads more easily. The study’s findings suggest that the structural differences between the two viruses' RBDs may also contribute to this increased transmission rate.

The researchers found that certain structural features in SARS-CoV-2’s RBD, such as its higher hydrophobicity (tendency to repel water), might explain why it folds more quickly in the absence of force. However, when force is applied, these same features could make it more prone to misfolding.
 
Conclusions
This study provides a valuable glimpse into the microscopic world of viral protein folding. By comparing how SARS-CoV-1 and SARS-CoV-2 RBDs fold under stress, the researchers uncovered important differences that may help explain why COVID-19 spread so rapidly across the globe. The sensitivity of SARS-CoV-2’s RBD to external forces could be a weakness that future treatments could exploit. By targeting these misfolding pathways, researchers may find new ways to disrupt the virus’s ability to infect cells.
 
The study’s insights into protein folding could also have broader implications for other diseases where protein misfolding plays a role, such as neurodegenerative conditions.
 
The study findings were published in the peer-reviewed journal: Biomolecules.
https://www.mdpi.com/2218-273X/14/10/1327
 
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https://www.thailandmedical.news/news/breaking-italian-and-american-study-claims-that-sars-cov-2-has-evolved-to-withstand-higher-temperatures