Molecular interactions accounting for protein denaturation by urea

Urea destabilizes proteins when added to aqueous solutions. To study its molecular mechanism we perform explicit all-atom molecular dynamics simulations of unrestrained poly-glycine, poly-alanine, and poly-leucine monomers as well as of extended poly-alanine and poly-leucine dimers. We show that poly-leucine monomers become less compact when urea is added to water whereas poly-glycine and poly-alanine monomers are only weakly affected by this co-solvent. Consistent with these results, we find that only the potential of mean force (PMF) of extended poly-leucine dimers changes significantly when urea is added to water. To rationalize these observations, we perform detail analysis of extended dimers. Urea is found to occupy positions between leucine's side chains that are not accessible to water. This allows extra van der Waals interactions between urea and side-chains to be formed which favor the monomeric state. In contrast, urea-solvent interactions are found to favor the dimeric state. The sum of these two energetic terms, i.e., urea-peptide and urea-solvent, provides the enthalpic driving force for urea denaturation. We show here that this enthalpy correlates with the potential of mean force of poly-leucine dimers. Moreover, the framework developed here is general and may be used to provide insights into effects of other small molecules on protein interactions.