Hidden complexity of free energy surfaces for peptide (protein) folding

An understanding of the thermodn. and kinetics of protein folding requires a knowledge of the free energy surface governing the motion of the polypeptide chain.  Because of the many degrees of freedom involved, surfaces projected on only 1 or 2 progress variables are generally used in descriptions of the folding reaction.  Such projections result in relatively smooth surfaces, but they could mask the complexity of the unprojected surface.  Here, the authors introduce an approach to det. the actual (unprojected) free energy surface and apply it to a 16-residue peptide, the 2nd β-hairpin of streptococcal protein G, which has been used as a model system for protein folding.  The surface was represented by a disconnectivity graph calcd. from a long equil. folding-unfolding trajectory.  The denatured state was found to have multiple low free energy basins.  Nevertheless, the peptide showed exponential kinetics in folding to the native basin.  Projected surfaces obtained from the present anal. had a simple form in agreement with other studies of the β-hairpin.  The hidden complexity found for the β-hairpin surface suggested that the std. funnel picture of protein folding should be revisited.