Roles of Urea and TMAO on the Interaction between Extended Non-Polar Peptides

In this study, we investigate the role played by urea and trimethylamine n-oxide (TMAO) in the stability of extended poly-alanine and poly-leucine dimers using all-atom molecular dynamics simulations and the explicit TIP3P water model. An umbrella sampling protocol is used to compute the potential of mean force (PMF) describing the interaction between these dimers at different concentrations of urea and TMAO. We show that while urea has a destabilizing effect on the interaction between poly-leucine chains, TMAO has an opposite effect. This is consistent with the use of urea as a denaturant and TMAO as an osmolyte stabilizing native structures of proteins. However, both cosolvents have no significant effect on the interaction between poly-alanine chains. To unravel the molecular mechanisms of TMAO and urea, we study enthalpic components of the energy, i.e., Lennard-Jones and electrostatic energies. No clear correlation is observed between changes in the enthalpy and the PMF, suggesting that an indirect mechanism mediated by water molecules could be responsible for the role of urea and TMAO. To provide insights into the interaction of urea and TMAO with the peptide dimer, we compute preferential interaction coefficients and spatial distributions of cosolvent and water around poly-alanine and poly-leucine. Urea and TMAO have a distinct distribution around the peptide with urea preferring to be located in its vicinity.