Free energy surface of the helical peptide Y(MEARA)(6)

The folding of the helical peptide Y(MEARA)(6) was studied by a series of m olecular dynamics simulations with an implicit solvation model that allowed sampling of a total of more than 4 mus, In the 44 runs at 360 K started fr om all-coil conformations the peptide assumed an ct-helical structure withi n the first 30 ns, with an average folding time of 10 ns. The free energy s urface shows that the coil to helix transition has a small barrier at the h elix nucleation step which consists of two to three i, i + 4 hydrogen bonds and does not show a strong preference along the sequence. On the helix sid e of the barrier, there is a very broad basin corresponding to conformation s having more than one helical turn. Although the pi -helical content is pr edominant, there is a nonnegligible percentage of conformations with one or more pi -helical turns stabilized in part by interactions between Met side chains. Control simulations with two different helical sequences, a 31-res idue polyalanine and A(5) (AAARA)(3) A, did not reveal a significant pi -he lix population, which indicates that the pi -helical content of Y(MEARA)(6) is not an artifact of the force field and solvation model. The folding, me chanism and free energy surface presented here are in agreement with previo us theoretical models and experimental data on different helical sequences, which suggest that they may be valid for the folding of helical peptides, in general.