Structural Ensemble ofan Intrinsically DisorderedPolypeptide.

Intrinsically disordered proteins (IDPs), which playkey rolesin cell signaling and regulation, do not display specific tertiarystructure when isolated in solution. Instead, they dynamically explorean ensemble of unfolded configurations, adopting more stable, orderedstructures only after binding to their ligands. Whether ligands induceIDP structural changes upon binding or simply bind to pre-existingconformers that are populated within the IDP’s structural ensembleis not well understood. Molecular simulations can provide informationwith the spatiotemporal resolution necessary to resolve these issues.Here, we report on the conformational ensemble of a 15-residue wild-typep53 fragment from the TAD domain and its mutant (TAD-P27L) obtainedby replica exchange molecular dynamics simulation using an optimized(fully atomistic, explicit solvent) protein model and the experimentalvalidation of the simulation results. We use a clustering method basedon structural similarity to identify conformer states populated bythe peptides in solution from the simulated ensemble. We show thatp53 populates solution structures that strongly resemble the ligand(MDM2)-bound structure, but at the same time, the conformational free-energylandscape is relatively flat in the absence of the ligand. [ABSTRACT FROM AUTHOR]