Unraveling the Interactions between Human DPP4 Receptor, SARS-CoV-2 Variants, and MERS-CoV, converged for Pulmonary Disorders Integrating through Immunoinformatics and Molecular Dynamics

Abstract

AbstractHuman coronaviruses like MERS CoV are known to utilize dipeptidyl peptidase 4 (DPP4), apart from angiotensin-converting enzyme 2(ACE2) as potential co-receptor for viral cell entry. DPP4, ubiquitous membrane-bound aminopeptidase is closely associated with elevation of disease severity in comorbidities. In SARS-CoV-2, there is inadequate evidence for combination of spike protein variants with DPP4, and underlying adversity in COVID19. To elucidate this mechanistic basis, we have investigated interaction of spike protein variants with DPP4 through molecular docking and simulation studies. The possible binding interactions between receptor binding domain (RBD) of different spike variants of SARS-CoV-2 and DPP4 have been compared with interactions observed in experimentally determined structure of complex of MERS-CoV with DPP4. Comparative binding affinity confers that Delta-CoV-2:DPP4 shows close proximity with MERS-CoV:DPP4, as depicted from accessible surface area, radius of gyration, number of hydrogen bonding and energy of interactions. Mutation in delta variant, L452R and T478K, directly participate in DPP4 interaction enhancing DPP4 binding. E484K in alpha and gamma variant of spike protein is also found to interact with DPP4. Hence, DPP4 interaction with spike protein gets more suitable due to mutation especially due to L452R, T478K and E484K. Furthermore, perturbation in the nearby residues Y495, Q474 and Y489 is evident due to L452R, T478K and E484K respectively. Virulent strains of spike protein are more susceptible to DPP4 interaction and are prone to be victimized in patients due to comorbidities. Our results will aid the rational optimization of DPP4 as a potential therapeutic target to manage COVID-19 disease severity.