Stabilizing $\alpha-$helicity of polypeptide in aqueous urea: Dipole orientation or hydrogen bonding?

TL;DR

This study uses extensive simulations to explore how aqueous urea influences polypeptide secondary structure stability, revealing a balance between dipole orientations and hydrogen bonding as key factors.

Contribution

It uncovers the microscopic mechanisms, specifically dipole-dipole interactions and hydrogen bonds, that govern polypeptide stability in urea, challenging previous assumptions.

Findings

Dipole orientations significantly influence polypeptide stability.

Hydrogen bonding plays a crucial role in urea-induced effects.

Counter-intuitive stabilization observed in certain polypeptides.

Abstract

Urea denatures proteins due to its strong tendency to dehydrate the first solvation shell via urea-residue preferential binding. However, even after extensive experimental and computational investigations, the influence of urea on the stability of secondary structures remains elusive. For example, contrary to the common understanding, experimental studies have indicated that specific polypeptides, such as poly-alanine or alanine-rich systems, may even show an improved tendency to form secondary structures in aqueous urea. We investigate this seemingly counter-intuitive behaviour using over 15$\mu$s long all-atom simulations. These results show how a delicate balance between the localized dipole orientations and hydrogen bonding dictates polypeptide solvation in aqueous urea. Our work establishes a structure-property relationship that highlights the importance of microscopic dipole-dipole orientations/interactions for the operational understanding of macroscopic protein solvation.