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

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 (ΣHF) for which experimental values are available. However, the calculated ΣHF 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 ΣHF 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 amoun...