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

TL;DR

This study explores how the DPP4 receptor interacts with SARS-CoV and MERS-CoV using simulations, revealing insights into their binding stability and energy barriers.

Contribution

The study provides novel insights into the role of DPP4 as a potential coreceptor for SARS-CoV through molecular simulations.

Findings

The SARS-CoV/DPP4 complex has a high free-energy barrier, indicating significant stability despite being energetically unfavorable.

The MERS-CoV/DPP4 complex is the most likely to form and least resistant to dissociation due to its low free-energy barrier.

There is an inverse relationship between electrostatic complementarity and complex stability due to competing interactions.

Abstract

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 (ΔF=6.77kBT), suggesting significant stability despite being energetically unfavorable. In contrast, the MERS‐CoV/DPP4 complex, with the lowest free‐energy barrier (ΔF=2.17kBT), was the most likely to form and the least resistant to dissociation. The SARS‐CoV/ACE2 complex demonstrated the highest Qbound, 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.

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