Unraveling DPP4 Receptor Interactions with SARS-CoV-2 Variants and MERS-CoV: Insights into Pulmonary Disorders via Immunoinformatics and Molecular Dynamics

The study titled “Unraveling DPP4 Receptor Interactions with SARS-CoV-2 Variants and MERS-CoV: Insights into Pulmonary Disorders via Immunoinformatics and Molecular Dynamics” provides significant insights into the interactions between the SARS-CoV-2 spike protein, its variants, and the DPP4 receptor.

Here’s a detailed summary:

Background and Objectives:

  • The study focuses on the DPP4 (dipeptidyl peptidase 4) receptor, which is utilized by human coronaviruses like MERS-CoV and potentially by SARS-CoV-2 as a co-receptor for cell entry. The research aims to investigate the interaction between spike protein variants of SARS-CoV-2 and DPP4, and how these interactions might affect disease severity, especially in patients with comorbidities​​.

Methodology:

  • Molecular docking and simulation studies were used to explore the binding interactions between the receptor-binding domain (RBD) of different SARS-CoV-2 spike variants and DPP4. The study compared these interactions with those observed in MERS-CoV. The molecular docking was performed using HADDOCK, a tool for generating accurate and informative models of protein-protein interactions​​.

Key Findings:

  • The Delta variant of SARS-CoV-2 (Delta-CoV-2) exhibited a binding affinity with DPP4 closely resembling that of MERS-CoV. This was determined based on parameters like accessible surface area, radius of gyration, and the number of hydrogen bonds at the interface.
  • Specific mutations in the Delta variant, namely L452R and T478K, were found to directly enhance the interaction with DPP4. Additionally, the E484K mutation in the Alpha and Gamma variants of the spike protein also interacted with DPP4.
  • These mutations led to changes in nearby residues (Y495, Q474, and Y489), suggesting that virulent strains of the spike protein are more prone to DPP4 interaction, potentially affecting patients with comorbidities​​.

Hydrogen Bonds Analysis:

  • The study analyzed the number of hydrogen bonds formed between DPP4 and various SARS-CoV-2 spike protein variants. A high number of hydrogen bonds, particularly in the Delta variant, indicated a stronger interaction with DPP4. These findings suggest that intermolecular hydrogen bonds are involved in high-affinity binding in these systems​​.

Interface Analysis:

  • The study also examined the closeness between DPP4 and the spike protein in different SARS-CoV-2 variants. The key residues forming the binding interface between MERS-CoV and DPP4 remained conserved throughout the simulation, indicating that the RBD of SARS-CoV-2 likely binds to DPP4 in a similar conformation as MERS-CoV. This analysis sheds light on the interaction mechanisms at the molecular level, which are crucial for understanding how different variants of the virus might affect binding to DPP4​​.

In conclusion, this study offers critical insights into how SARS-CoV-2 variants, particularly the Delta variant, interact with the DPP4 receptor. These interactions may have significant implications for the severity of COVID-19, especially in patients with comorbidities, highlighting the importance of DPP4 as a potential therapeutic target in managing COVID-19.

Read More: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10612102/

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