Correlated long-distance dynamics modulate monoclonal antibody binding resistance in flaviviral envelope pretein domain-3: A molecular dynamics simulations study

Numerous monoclonal antibody (MAb) binding resistant mutations have been localized to the envelope protein domain-3 (ED3) of flaviviruses. Previously it was shown that regions constituting antibody binding sites of dengue-2 (DEN2) and West Nile virus (WNV) ED3 were energetically coupled with the interior of the protein. Protein-protein interactions are characterized by perturbation of residue dynamics at the binding interface and at regions physically far from the binding site. Based on above I hypothesized that mutations leading to resistance from antibody binding would perturb dynamics associated with binding at the interface and therefore also the correlation in motions with the interior of the protein. I investigated this hypothesis by analyzing the dynamics of wild type and mutant ED3s of DEN2 and WNV using molecular dynamics (MD) simulations and principal components analysis (PCA). I found that residues constituting binding sites for the MAbs, when mutated, drastically perturb the organized motions in the peptide. Cross-correlation analysis of the dynamics established that the MAb binding resistant mutations perturbed correlated long distance dynamics globally. Computationally this analysis aids in locating the MAb binding regions in flaviviral ED3s through simple analysis wild type and mutant MD trajectories.