Molecular dynamics simulations of the protein model Trp-cage in 42% trifluoroethanol (TFE)-water at 298 K have been carried out with the goal of exploring peptide hydrogen-solvent fluorine nuclear spin cross-relaxation. The TFES model of TFE developed in a previous work was used with the TIPSP-Ew model of water. System densities and component translational diffusion coefficients predicted by the simulations were within 20% of the experimental values. Consideration of the calculated relative amounts of TFE and water surrounding the hydrogens of Trp-cage indicated that the composition of the solvent mixture beyond similar to 1.5 nm from the van der Waals surface of the peptide is close to the composition of the bulk solvent, but as observed by others, TFE accumulates preferentially near the peptide surface. In the simulations, 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 be slowed near the surface of the peptide. Depending on the location in the structure, TFE molecules form complexes with the peptide that may persist for up to similar to 7 ns. Many of the peptide spin-solvent fluorine cross-relaxation parameters (Sigma(HF)) for which experimental values are available are reasonably well-predicted from the simulations. However, the calculated Sigma(HF) values were too small for some hydrogens of the 6Trp indole ring and the amino acid hydrogens near this residue in the native structure, whereas Sigma(HF) values for hydrogens on the side chains of 1Asn, 4Ile, and 7Leu are too large. In 42% TFE-water, persistent conformations of Trp-cage are found, which differ from the conformation found in water by the orientation of the 3Tyr ring.