Noncovalent interactions such as hydrogen bonding, ion pair interactions and van der Waals interactions make the folded states of proteins marginally more stable than the unfolded states. The equilibrium between the folded and unfolded states can readily be shifted by cosolvents such as urea. Such experiments provide valuable thermodynamic and structural insights into the protein folding phenomenon. A fundamental understanding of the nature of interactions between the protein and aqueous urea is necessary. Free energy calculations on the unfolding of Trp-cage miniprotein demonstrates the importance of urea-aromatic interactions in facilitating the unfolding of the protein. The nature of such urea-aromatic interactions was characterized using molecular dynamics simulations, quantum mechanical calculations and analysis of experimental structures of urea transporters and proteins crystalized in the presence of urea or urea derivatives. We show that stacking type interactions between urea and aromatic residues are responsible for strong interaction between the two. Additionally, NH-π and hydrogen bonding interactions also contribute to the stabilization of the solvent exposed aromatic residues in the presence of urea.

Urea-aromatic interactions: Protein unfolding to urea transporters

256th National Meeting (2018)

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