Role of the DPP4 Receptor in SARS-CoV Entry: Insights From Docking and Molecular Dynamics Simulations.

Protein-receptor interactions play a critical role in viral entry and pathogenesis. While ACE2 is the primary receptor for SARS-CoV, the role of DPP4 as potential coreceptor remains underexplored. This study investigates the binding mechanisms and dissociation dynamics of the SARS-CoV/DPP4, SARS-CoV/ACE2 and MERS-CoV/DPP4 complexes using molecular docking and molecular dynamics simulations. The SARS-CoV/DPP4 complex exhibited the highest free-energy barrier ( $\Delta F=6.77k_{B}T$ ), suggesting significant stability despite being energetically unfavorable. In contrast, the MERS-CoV/DPP4 complex, with the lowest free-energy barrier ( $\Delta F=2.17k_{B}T$ ), was the most likely to form and the least resistant to dissociation. The SARS-CoV/ACE2 complex demonstrated the highest $Q_{\text{bound}}$ , reflecting well-organized interfacial side chains that facilitate hydrogen bonding, yet its relatively low free-energy barrier and dissociation temperature made it prone to dissociation. These findings highlight an inverse relationship between electrostatic complementarity and protein-protein complex stability, where increased electrostatic complementarity correlates with reduced stability due to frustration from competing interactions. While DPP4 may serve as a coreceptor for SARS-CoV, its interaction is constrained by significant energy barriers, suggesting it may only occur under specific biological conditions or alternative binding pathways.