Urea-water solvation of protein side chain models

Abstract

Aqueous urea stabilizes the unfolded states of protein due to their ability to solvate both hydrophilic and hydrophobic residues favorably. The nature of interactions that stabilize different types of amino acid side chains in their solvent exposed state is still not understood. To gain insights into the molecular level details of urea interactions with proteins in their unfolded states, we have performed atomistic molecular dynamics simulations and free energy calculations using the thermodynamic integration method on model systems representing side chains of all amino acids in different solvent environments (water and varying concentrations of aqueous urea). A systematic analysis of structural, energetic and dynamic parameters has been done to understand the detailed atomistic mechanism. The main aim of the current study is to unravel the nature of urea-amino acid interactions by emphasizing on the chemical nature of amino acid side chain models. The preferential interactions of urea over water with each side chain and backbone model systems in various concentrations of aqueous urea were quantified using the two-domain model, and it is validated by mean lifetime calculations. Interestingly, almost all amino acids showed a preference for urea over water. The order of preferences depending on the chemical nature of the amino acids is obtained with the aromatic groups exhibiting the highest preferences followed by hydrophobic groups, followed by amides and basic groups, and the least by nucleophilic groups. The extensive energetic analysis revealed, these preferential interactions are enthalpically and entropically driven and are dominated by dispersion effects. Spatial density distributions and radial distribution analyses provide insights to understand the different modes and urea orientation towards preferred sites of interactions by which urea-protein interactions stabilize proteins in their unfolded states by forming favorable interactions with exposed amino acids side chains.