The dominant interaction between peptide and urea is electrostatic in nature: a molecular dynamics simulation study

Area of Science:

• Biochemistry
• Chemical Physics
• Computational Biology

Background:

• Urea is a known denaturant of proteins, but its precise molecular mechanism remains under investigation.
• Understanding solvent-peptide interactions is crucial for comprehending protein folding and denaturation.

Purpose of the Study:

• To investigate the conformational equilibrium of a model peptide in aqueous urea solutions using molecular dynamics simulations.
• To elucidate the role of urea-peptide interactions, particularly hydrogen bonding and hydrophobic effects, in protein denaturation.

Main Methods:

• Molecular dynamics (MD) simulations were employed to study a blocked valine peptide in water and aqueous urea.
• Pair correlation functions were used to analyze the local concentration of urea around the peptide.
• Umbrella sampling was utilized to compute the potential of mean force (PMF) for solvation.

Main Results:

• Simulations revealed an enhanced concentration of urea in the vicinity of the peptide compared to water.
• Urea exhibited stronger hydrogen bonding with the peptide backbone than water, favoring a helical conformation.
• Potential of mean force calculations showed minimal, difficult-to-quantify differences in solvation between urea and water.

Conclusions:

• Urea denatures proteins by preferentially forming hydrogen bonds with the peptide backbone.
• These interactions reduce the energetic barrier for exposing protein residues to the solvent, promoting unfolding.
• Hydrophobic interactions do not appear to significantly change in urea solution, suggesting a dominant role for hydrogen bonding in urea's denaturing effect.