Elucidating the conformational dynamics of histo-blood group antigens and their interactions with the rotavirus spike protein through computational lens

In the present study, we investigated the conformational dynamics of histo-blood group antigens (HBGAs) and their interactions with the VP8* domain of four rotavirus genotypes (P[4], P[6], P[19], and P[11]) utilizing all-atom molecular dynamics simulations in explicit water. Our study revealed distinct changes in the dynamic behavior of the same glycan due to linkage variations. We observed that LNFPI HBGA having a terminal beta linkage shows two dominant conformations after complexation, whereas only one was obtained for LNFPI with a terminal alpha linkage. Interestingly, both variants displayed a single dominant structure in the free state. Similarly, LNT and LNnT show a shift in their dihedral linkage profile between their two terminal monosaccharides because of a change in the linkage from beta(1-3) to beta(1-4). The molecular mechanics generalized Born surface area (MM/GBSA) calculations yielded the highest binding affinity for LNFPI(beta)/P[6] (-13.93 kcal/mol) due to the formation of numerous hydrogen bonds between VP8* and HBGAs. LNnT binds more strongly to P[11] (-12.88 kcal/mol) than LNT (-4.41 kcal/mol), suggesting a single change in the glycan linkage might impact its binding profile significantly. We have also identified critical amino acids and monosaccharides (Gal and GlcNAc) that contributed significantly to the protein-ligand binding through the per-residue decomposition of binding free energy. Moreover, we found that the interaction between the same glycan and different protein receptors within the same rotavirus genogroup influenced the micro-level dynamics of the glycan. Overall, our study helps a deeper understanding of the H-type HBGA and rotavirus spike protein interaction.Communicated by Ramaswamy H. Sarma

Automated summary

In this study, the conformational dynamics of histo-blood group antigens and their interactions with VP8* domain of rotavirus genotypes were investigated using molecular dynamics simulations. The study revealed changes in the dynamic behavior of glycans due to linkage variations. The binding affinity was calculated, revealing the impact of glycan linkage on binding. Additionally, key amino acids and monosaccharides contributing to protein-ligand binding were identified.