Conventional wisdom has it that the presence of disordered regions in the three-dimensional structures of polypeptides not only does not contribute significantly to the thermodynamic stability of their folded state, but, on the contrary, that the presence of disorder leads to a decrease of the corresponding proteins' stability. We have performed extensive 3.4 μs long folding simulations (in explicit solvent and with full electrostatics) of an undecamer peptide of experimentally known helical structure, both with and without its disordered (four residue long) C-terminal tail. Our simulations clearly indicate that the presence of the apparently disordered (in structural terms) C-terminal tail, increases the thermodynamic stability of the peptide's folded (helical) state. These results show that at least for the case of relatively short peptides, the interplay between thermodynamic stability and the apparent structural stability can be rather subtle, with even disordered regions contributing significantly to the stability of the folded state. Our results have clear implications for the understanding of peptide energetics and the design of foldable peptides. © 2010 Patapati, Glykos.
Patapati, K. K., & Glykos, N. M. (2010). Order through disorder: Hyper-mobile C-terminal residues stabilize the folded state of a helical peptide. A molecular dynamics study. PLoS ONE, 5(12). https://doi.org/10.1371/journal.pone.0015290