Binding of transmissible gastroenteritis virus and porcine respiratory coronavirus to human and porcine aminopeptidase N receptors as an indicator of cross-species transmission.

Abstract

Coronaviruses have the ability to overcome interspecies barriers and adapt to new hosts, posing significant epidemic risks in cases of zoonotic transmission to humans. A critical factor in this process is the interaction between coronavirus spike proteins and host cell surface receptors, which plays an important role in infection and disease progression. This study focused on two representatives of coronaviruses: transmissible gastroenteritis virus (TGEV) and its mutant, porcine respiratory coronavirus (PRCV), both of which naturally cause disease in pigs. A phylogenetic analysis of previously identified strains of these viruses was performed, and the conservation of receptor-binding domain (RBD) sequences within their spike proteins was evaluated. In silico modeling was performed for complexes of the RBDs from 16 virus strains with porcine aminopeptidase N (APN), as well as for putative complexes with the human APN receptor. The binding free energy of these modeled complexes was evaluated, along with the impact of more than 500 theoretical mutations in the RBD. The computational results suggest that the TGEV 133 strain exhibits the highest affinity for both porcine and human receptors, with only two additional mutations required to further enhance this affinity. Molecular dynamics simulations were conducted for porcine and human APN complexes with known TGEV strains (Purdue and 133) as well as a theoretical mutated strain. These simulations reveal differences in the dynamic behavior of complexes with porcine and human receptors and support the hypothesis that mutagenesis at a few key amino acid residues in the RBD could enable TGEV to achieve affinity for human APN comparable to that of its natural host receptor. The findings underscore a theoretical risk of zoonotic transmission of these coronaviruses to humans, emphasizing the importance of further monitoring these pathogens.