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The Viral Protein 35 (VP35), a crucial protein of the Zaire Ebolavirus (EBOV), interacts with a plethora of human proteins to cripple the human immune system. Despite its importance, the entire structure of the tetrameric assembly of EBOV VP35 and the means by which it antagonizes the autophosphorylation of the kinase domain of human protein kinase R (PKR K ) is still elusive. We consult existing structural information to model a tetrameric assembly of the VP35 protein where 93% of the protein is modeled using crystal structure templates. We analyze our modeled tetrameric structure to identify interchain bonding networks and use molecular dynamics simulations and normal-mode analysis to unravel the flexibility and deformability of the different regions of the VP35 protein. We establish that the C-terminal of VP35 (VP35 C ) directly interacts with PKR K to prevent it from autophosphorylation. Further, we identify three plausible VP35 C -PKR K complexes with better affinity than the PKR K dimer formed during autophosphorylation and use protein design to establish a new stretch in VP35 C that interacts with PKR K . The proposed tetrameric assembly will aid in better understanding of the VP35 protein, and the reported VP35 C -PKR K complexes along with their interacting sites will help in the shortlisting of small molecule inhibitors.

Ebola Virus VP35 Protein: Modeling of the Tetrameric Structure and an Analysis of Its Interaction with Human PKR