MD simulations of
the peptide Trp-cage dissolved in 28%
hexafluoroisopropanol
(HFIP)-water have been carried out at 298 K with the goal of exploring
peptide hydrogen–solvent fluorine nuclear spin cross-relaxation.
The work was motivated by the observation that most experimental fluoroalcohol-peptide
cross-relaxation terms at 298 K are small, both positive and negative,
and not always well predicted from simulations. The cross-relaxation
terms for hydrogens of the caged tryptophan residue of Trp-cage are
substantially negative, a result consistent with simulations. It was
concluded that hexafluoroisopropanol interactions near this part of
the peptide are particularly long-lived. While both HFIP and water
are present in all regions of the simulation box, the composition
of the solvent mixture is not homogeneous throughout the system. HFIP
generally accumulates near the peptide surface, while water molecules
are preferentially found in regions that are more than 1.5 nm from
the surface of the peptide. However, some water remains in higher-than-expected
amounts in the solvent layer surrounding 6Trp, 9Asp, Ser13, and Ser14
residues in the helical region of Trp-cage. As observed in simulations
of this system at 278 K, HFIP molecules aggregate into clusters that
continually form and re-form. Translational diffusion of both HFIP
and water appears to be slowed near the surface of the peptide with
reduction in diffusion near the 6Trp residue 2- to 3-fold larger than
calculated for solvent interactions with other regions of Trp-cage.