Effect of hexafluoroisopropanol alcohol on the structure of melittin: A molecular dynamics simulation study

The molecular mechanism by which HFIP stabilizes the alpha-helical
structure of peptides is not well understood. In the present study, we
use melittin as a model to gain insight into the details of the
atomistic interactions of HFIP with the peptide. We have performed
extensive comparative molecular dynamics simulations (up to 100 nsec) in
the absence and in the presence of HFIP. In agreement with recent NMR
experiments, the simulations show rapid loss of tertiary structure in
water at pH 2 but much higher helicity in 35\% HFIP. The MD simulations
also indicate that melittin adopts a highly dynamic global structure in
35\% HFIP solution with two a-helical segments sampling a wide range of
angular orientations. The analysis of the HFIP distribution shows the
tendency of HFIP to aggregate around the peptide, increasing the local
cosolvent concentration to more than two times that in the bulk
concentration. The correlation of local peptide structure with HFIP
coating suggests that displacement of water at the peptide surface is
the main contribution of HFIP in stabilizing the secondary structure of
melittin. Finally, a stabilizing effect promoted by the presence of
counter-ions was also observed in the simulations.