Information-Entropy-Based Single Amino Acid Polymorphism Analysis Reveals Functional Variance of Enterovirus 2A Proteases

作者：Xi Zhu, Zhoule Guo, Qiong Wang, Xing‐Yi Ge, Yang Xiao, Ye Qiu · 发表于：Microorganisms · 年份：2026 · DOI：10.3390/microorganisms14081616 · 研究领域：Viral Infections and Immunology Research、Respiratory viral infections research、Animal Disease Management and Epidemiology

Enterovirus alphacoxsackie (EV-A) is a highly diverse viral species containing at least 25 serotypes with diverse biological and clinical characteristics. EV-A can cause diseases ranging from asymptomatic infections to severe neurological disorders, as well as mucocutaneous diseases such as hand, foot, and mouth disease. 2A, a cysteine protease expressed by EV-A, plays critical roles in virus–host interactions. Although 2A orthologs of different EV-A serotypes share consistent protease-catalytic motifs and cleavage patterns, they show functional diversity in interacting with cellular proteins, probably due to distinct protease-independent activities determined by the single amino acid polymorphisms (SAPs) among different 2A orthologs. However, routine sequence alignment and phylogenetic analysis can hardly identify the key SAP sites (kSAPs) contributing to the functional variance, mainly due to the high conservation of the proteins and the unequal weight of SAPs in determining protein function. Herein, we developed Single Amino Acid Polymorphism Statistics (SAAPS), an information-entropy (IE)-based algorithmic pipeline, to identify the functional kSAPs of EV-A 2A. The core principle of the algorithm is that the IE of the kSAPs can be neither too low (highly conserved sites not leading to variance) nor too high (random neutral mutations). Using SAAPS, we identified 56 kSAPs from 2A of 25 EV-A serotypes. Based on the kSAPs, the 2As can be clustered into three major groups with ...