Protein-protein and protein-lipid interactions form a basis for protein function. Viruses often express a simple genome encoding multifunctional proteins. The Ebola virus lipid-binding matrix protein VP40 is an ideal example of a multifunctional protein, being involved in viral budding as a filamentous structure and an octameric ring facilitating transcription. Binding to membranous lipids triggers conformational rearrangement of the N- and C-terminal domains of VP40 that precedes filament formation and budding. Several interdomain contacts have been identified that regulate the formation of filaments, affect dimer stability and govern conformational dynamics.<br/><br/>In the present work, computational simulations – Monte Carlo (Rosetta) and molecular dynamics (MM-GB/PBSA based alanine scanning) were used to ascertain critical interdomain residues that affect the dimerization of the VP40 monomer. The computational results were validated by comparison with microscale thermophoresis experiments performed using mutants deemed important by the in-silico mutagenesis experiments.

Elucidating determinants of Ebola virus VP40 dimerization using computational simulations and biophysical approaches

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