Disorder-Order Transitions in Conformational Selection of a Peptide by Ebola Virus Nucleoprotein

This study presents parallel-tempering lattice Monte Carlo simulations based on the side-chain-only (SICHO) model for calculating the conformational landscape of a 28-residue intrinsically disordered peptide extracted from the Ebola virus protein VP35. The central issue is the applicability of the SICHO potential energy function and in general coarse-grained (CG) representations of intermediate resolution for modeling large-scale conformational heterogeneity that includes both folded and unstructured peptide states. Crystallographic data shows that the peptide folds in a 4₁₀-helix-turn-3₁₀-helix topology upon complex formation with the Ebola virus nucleoprotein, whereas in isolation, the peptide transitions to a disordered conformational ensemble as observed in circular dichroism experiments. The simulation reveals a potential of mean force that displays conformational diversity along the helix-forming reaction coordinate consistent with disorder-order transitions, yet unexpectedly the bound topology is poorly sampled, and a population shift to an unstructured state incurs a significant free-energy penalty. Applying an elastic network interpolation model suggests a hybrid binding mechanism through conformational selection of the 4₁₀-helix followed by an induced fit of the 3₁₀-helix. A comparison of the CG model with previously reported all-atom CHARMM-based simulations highlights a lattice-based approach that is computationally fast and with the correct parameterization yields good resolution to modeling conformational plasticity.