Stabilizing α-Helicity of a Polypeptide in Aqueous Urea: Dipole Orientation or Hydrogen Bonding?

We propose a mechanismfor alpha-helix folding of polyalaninein aqueous urea that reconciles experimental and simulation studies.Over 15 mu s long, all-atom simulations reveal that, upon dehydratingthe protein's first solvation shell, a delicate balance betweenlocalized urea-residue dipole interactions and hydrogen bondsdictates polypeptide solvation properties and structure. Our workclarifies the experimentally observed tendency of these alanine-richsystems to form secondary structures at low and intermediate ureaconcentrations. Moreover, it is consistent with the commonly acceptedhydrogen-bond-induced helix unfolding, dominant at high urea concentrations.These results establish a structure-property relationship highlightingthe importance of microscopic dipole-dipole orientations/interactionsfor the operational understanding of macroscopic protein solvation.

Automated summary

We propose a mechanism that explains the folding of polyalanine in aqueous urea. Our simulations show that a balance between urea-residue dipole interactions and hydrogen bonds determines the solvation properties and structure of the polypeptide. This mechanism explains the tendency of alanine-rich systems to form secondary structures at low and intermediate urea concentrations, and the unfolding of helix structures at high urea concentrations. These findings highlight the importance of dipole-dipole interactions for understanding protein solvation.