Examination of Trifluoroethanol Interactions with Trp-Cage through MD Simulations and Intermolecular Nuclear...

Molecular dynamics simulations of the protein model Trp-cage in 42% 2,2,2-trifluoroethanol (TFE)-water at 318 K have been carried out with the goal of exploring solvent fluorine-peptide hydrogen nuclear spin cross-relaxation. TFE5 and TFE6 models of TFE developed in previous work from this laboratory were used with the TIP5PE model of water. System densities and component translational diffusion coefficients were well predicted by the simulations, as were many of the cross-relaxation parameters (Σ_HF) for which experimental values are available. However, the calculated Σ_HF values were too small for some hydrogens of the Trp6 indole ring and for amino acid hydrogens near this residue in the native structure. Simulations carried out with unfolded versions of Trp-cage suggest that underestimates of Σ_HF are the result of insufficient sampling of conformational motions that expose these hydrogens to interactions with solvent molecules during simulations of the native peptide. Consideration of the relative amounts of TFE and water surrounding the Trp-cage structure indicates that the composition of the solvent mixture at distances beyond ∼1.5 nm from the surface of the peptide is close to the composition of the bulk solvent, but, as observed by others, TFE tends to accumulate preferentially near the surface of the peptide. Both TFE and water molecules make contacts with the peptide surface; water molecules predominate in contacts with the peptide backbone atoms, and TFE molecules generally preferentially interact with side chains. Translational diffusion of solvent molecules appears to slow down near the surface of the peptide.