Equilibrium and folding simulations of NS4B H2 in pure water and water/2,2,2-trifluoroethanol mixed solvent: Examination of solvation models

The structural stability and preference of a protein are highly sensitive to the environment accommodating it. In this work, the solvation effect on the structure and folding dynamics of a small peptide, NS4B H2, was studied by computer simulation. The native structure of NS4B H2 was solved previously in 50 % v/v water/2,2,2-trifluoroethanol (TFE) mixed solvent. In this work, both pure water and water/TFE cosolvent were utilized. The force field parameters for water were taken from the TIP3P water model, and those for TFE were generated following the routine of the general AMBER force field (GAFF). The simulated structure of NS4B H2 in the mixed solvent is quite in line with experimental data, while in pure water it undergoes a large structural deformation. The generalized Born (GB) model was also investigated by tuning the dielectric constant to match experimental measurements. However, the results show that its performance was less satisfactory. Two independent direct folding simulations of NS4B H2 in explicit water/TFE cosolvent were carried out, both of which resulted in successful folding. Investigation of the distribution of solvent molecules around the peptide indicates that folding is triggered by the aggregation of TFE on the peptide surface.