COVID-19 News: Italian Study Validates That Spike Proteins Of SARS-CoV-2 Bind to Hemoglobin

COVID-19 News: The emergence of various coronavirus-related diseases, such as Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and the ongoing COVID-19 pandemic, has underscored the urgent need for a comprehensive understanding of the biological and biochemical behavior of these pathogens. Among the key proteins of SARS-CoV-2, the Spike protein has garnered significant attention. Extensive research has focused on its interaction with the human ACE2 receptor, which is crucial for viral entry into host cells. However, recent findings suggest that the Spike protein may interact with various human proteins, with hemoglobin emerging as a potential target.


Results of the WTMFs simulations. All panels show the 1D energy profile (top left), the FES for the RBD/Hb interaction (bottom left) and the extracted structure of the global minimum (right; only BB beads have been used to represent the complexes. Heme residues are also shown as red spheres). The yellow star in each FES indicates the global minimum. A) RBD/HbAR-state. B) RBD/HbAT-state. C) RBD/HbFR-state. D) RBD/HbFT-state.

In fact, numerous past studies and COVID-19 News reports had already shown that SARS-CoV-2 binds to hemoglobin but unfortunately due to bastards working at Facebook and the American charlatans it employed as fact-checkers and certain garbage male Italian journalists and British ‘experts’, many of these studies were labelled as fake news by these dogs!
 
https://www.thailandmedical.news/news/must-read-research-reveals-that-covid-19-attacks-hemoglobin-in-red-blood-cells,-rendering-it-incapable-of-transporting-oxygen--current-medical-protoco
 
https://www.thailandmedical.news/news/covid-19-news-study-validates-that-sars-cov-2-structural-proteins-binds-to-hemoglobin-and-myoglobin-causing-hemoglobin-and-iron-dysmetabolism
 
https://www.thailandmedical.news/news/brazilian-study-confirms-that-sars-cov-2-proteins-binds-not-only-to-metabolites-of-hemoglobin-like-biliverdin-but-also-to-hemoglobin-itself
 
A new groundbreaking study conducted by scientists from the University of Ferrara and the University of Padova in Italy that employs advanced molecular dynamics techniques to investigate the interaction between hemoglobin and the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, has not only validated that SARS-CoV-2 spike proteins not only bind to hemoglobin but also sheds light on the molecular intricacies of this binding and its potential implications for COVID-19 pathophysiology.< ;br />  
The Role of the Spike Protein
The Spike (S) protein of SARS-CoV-2 plays a pivotal role in the virus's ability to infect host cells. It achieves this by binding to the human angiotensin-converting enzyme 2 (ACE2) receptor through its Receptor Binding Domain (RBD). This interaction serves as the initial trigger for viral infection, particularly in pulmonary epithelial cells, where COVID-19 primarily manifests.
 
Moreover, the Spike protein has been a focal point for vaccine development, with various vaccines targeting it. The emergence of different variants during the pandemic underscores the importance of understanding the Spike protein's behavior as it relates to infectivity and lethality.
 
Beyond ACE2: Spike Protein Interactions
While the interaction between the Spike protein and ACE2 is well-established, recent research has suggested that the Spike protein might also interact with other host proteins. One such interaction of considerable interest is the potential binding of the Spike protein to hemoglobin, a critical component of red blood cells.
 
Hemoglobin and its Role in Oxygen Transport
Hemoglobin (Hb) is a well-characterized protein responsible for oxygen transport to tissues and the removal of carbon dioxide. Structurally, Hb is a hetero-tetrameric globular protein with a distinctive ellipsoidal shape. It comprises two α and two β subunits, each containing a heme cofactor responsible for oxygen and carbon dioxide transport.
 
During development, the switch from fetal hemoglobin (HbF) to adult hemoglobin (HbA) occurs. HbF differs from HbA in that it contains γ subunits instead of β subunits. HbF has a higher affinity for oxygen, allowing the fetus to extract oxygen efficiently from the mother's blood. In normal adults, HbF expression is minimal, but it plays a crucial role in conditions like β-thalassemia, where the synthesis of HbA is reduced or absent. Increasing HbF production can serve as a therapeutic strategy in such cases.
 
Spike Protein Interaction with Hemoglobin
In 2021, researchers proposed that various SARS-CoV-2 proteins, including the Spike protein, could bind to HbA. They observed that preincubating cells with HbA reduced both virus infection and replication. Biochemical experiments suggested that the RBD was the most probable binding site for HbA. These findings have spurred further exploration of the interaction between hemoglobin and the Spike protein.
 
Advanced Molecular Dynamics Techniques
To gain deeper insights into the interaction between the RBD and hemoglobin (both HbA and HbF), the Italian research team employed advanced molecular dynamics (MD) techniques. They used a coarse-grained (CG) approximation known as MARTINI, which simplifies the representation of molecules by grouping atoms into "beads," enabling longer simulations without the need for high-performance computing.
 
In their simulations, the researchers assessed both the energy and geometry of the RBD-HbA and RBD-HbF interactions. The results suggested that the most probable conformations interacting with the RBD were the T-state for HbA and R-state for HbF. These findings aligned with earlier biochemical data and provided a new perspective on why RBD/HbA might not adsorb carbon monoxide effectively.

Furthermore, they identified that the interaction between hemoglobin and the RBD occurred primarily through the αnβ(γ)n surface, exhibiting highly favorable interactions. In co-culture experiments with epithelial cells, a significant reduction in the pro-inflammatory effects of the Spike protein was observed when HbA and HbF were present.
 
Implications and Future Research
This study offers compelling evidence of a direct binding between hemoglobin and the Spike protein, shedding light on the molecular underpinnings of this interaction. Importantly, the binding energy calculated through MD simulations surpassed that obtained solely through docking simulations, emphasizing the importance of thorough molecular dynamics exploration.
 
Additionally, this study marks a pioneering use of the funnel metadynamics strategy for the study of protein-protein interactions. While this approach provides valuable insights, it has its limitations, such as the use of an elastic network and the inherent loss of some structural information due to the CG approximation.
 
The findings suggest that the effects of the Spike protein on the hematopoietic system warrant further investigation, especially in erythroid cellular systems and individuals undergoing COVID-19 vaccination. It's crucial to understand how the production of the Spike protein, which occurs not only during infection but also post-vaccination, may impact hemoglobin and red blood cell function.
 
Conclusion
In summary, the Italian study conducted by the University of Ferrara and the University of Padova validates the binding of the Spike protein of SARS-CoV-2 to hemoglobin. Through advanced molecular dynamics techniques, the study provides valuable insights into the energy and geometry of this interaction, further substantiating the hypothesis of a direct binding between these two molecules. This research contributes to our understanding of COVID-19 pathophysiology and highlights the potential effects of the Spike protein on the hematopoietic system, emphasizing the need for continued investigation in this area.
 
The study findings were published in the peer reviewed International Journal of Biological Macromolecules.
https://www.sciencedirect.com/science/article/pii/S0141813023039855
 
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