Structural Differences between the Avian and Human H7N9 Hemagglutinin Proteins Are Attributable to Modifications in Salt Bridge Formation: A Computational Study with Implications in Viral Evolution

Abstract

Influenza A hemagglutinin (HA) is a homotrimeric glycoprotein composed of a fibrous globular stem supporting a globular head containing three sialic acid binding sites responsible for infection. The H7N9 strain has consistently infected an avian host, however, the novel 2013 strain is now capable of infecting a human host which would imply that the HA in both strains structurally differ. A better understanding of the structural differences between the avian and human H7N9 strains may shed light into viral evolution and transmissibility. In this study, we elucidated the structural differences between the avian and human H7N9 strains. Throughout the study, we generated HA homology models, verified the quality of each model, superimposed HA homology models to determine structural differences, and, likewise, elucidated the probable cause for these structural differences. We detected two different types of structural differences between the novel H7N9 human and representative avian strains, wherein, one type (Pattern-1) showed three non-overlapping regions while the other type (Pattern-2) showed only one non-overlapping region. In addition, we found that superimposed HA homology models exhibiting Pattern-1 contain three non-overlapping regions designated as: Region-1 (S157 ₁-A160 ₁); Region-3 (R262 ₁-S265 ₁); and Region-4 (S270 ₁-D281 ₁), whereas, superimposed HA homology models showing Pattern-2 only contain one non-overlapping region designated as Region-2 (S137 ₁-S145 ₁). We attributed the two patterns we observed to either the presence of salt bridges involving the E114 ₁ residue or absence of the R141 ₁:D77 ₁ salt bridge. Interestingly, comparison between the human H7N7 and H7N9 HA homology models showed high structural similarity. We propose that the putative absence of the R141 ₁:D77 ₁ salt bridge coupled with the putative presence of the E114 ₁:R262 ₁ and E114 ₁:K264 ₁ salt bridges found in the 2013 H7N9 HA homology model is associated to human-type receptor binding. This highlights the possible significance of HA salt bridge formation modifications in viral infectivity, immune escape, transmissibility and evolution.