Peka Mykyta, Balatsky Viktor
Department of Molecular Biology and Biotechnology, School of Biology, V. N. Karazin Kharkiv National University, Kharkiv, Ukraine.
Genetics Laboratory, Institute of Pig Breeding and Agroindustrial Production, National Academy of Agrarian Sciences of Ukraine, Poltava, Ukraine.
PLoS One. 2025 May 27;20(5):e0325023. doi: 10.1371/journal.pone.0325023. eCollection 2025.
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.
冠状病毒有能力跨越种间屏障并适应新宿主，在人畜共患病传播给人类的情况下带来重大的流行风险。这一过程中的一个关键因素是冠状病毒刺突蛋白与宿主细胞表面受体之间的相互作用，其在感染和疾病进展中起重要作用。本研究聚焦于两种冠状病毒代表：传染性胃肠炎病毒（TGEV）及其突变体猪呼吸道冠状病毒（PRCV），它们在猪身上自然引发疾病。对这些病毒先前鉴定的毒株进行了系统发育分析，并评估了其刺突蛋白内受体结合域（RBD）序列的保守性。对来自16种病毒毒株的RBD与猪氨肽酶N（APN）的复合物以及与人类APN受体的假定复合物进行了计算机模拟。评估了这些模拟复合物的结合自由能，以及RBD中500多个理论突变的影响。计算结果表明，TGEV 133毒株对猪和人类受体均表现出最高亲和力，只需另外两个突变即可进一步增强这种亲和力。对猪和人类APN与已知TGEV毒株（普渡和133）以及一个理论突变毒株的复合物进行了分子动力学模拟。这些模拟揭示了与猪和人类受体的复合物在动态行为上的差异，并支持这样的假设，即RBD中几个关键氨基酸残基的诱变可使TGEV对人类APN产生与其天然宿主受体相当的亲和力。这些发现强调了这些冠状病毒人畜共患病传播给人类的理论风险，凸显了进一步监测这些病原体的重要性。
