Role of water on unfolding kinetics of helical peptides studied by molecular dynamics simulations

Molecular dynamics simulations have been carried out with four polypeptides, Ala₁₃, Val₁₃, Ser₁₃, and Ala₄Gly₅Ala₄, in vacuo and with explicit hydration. The unfolding of the polypeptides, which are initially fully α-helix in conformation, has been monitored during trajectories of 0.3 ns at 350 K. A rank of Ala < Val < Ser < Gly is found in the order of increasing rate of unwinding. The unfolding of Ala₁₃, and Val₁₃, is completed in hundreds of picoseconds, while that of Ser₁₃, is about one order of magnitude faster. The helix content of the peptide containing glycine residues falls to zero within a few picoseconds. Ramachandran plots indicate quite distinct equilibrium distributions and time evolution of dihedral angles in water and in vacuum for each residue type. The unfolding of polyalanine and polyvaline helices is accelerated due to solvation. In contrast, polyserine is more stable in water compared to vacuum, because its side chains can form intramolecular hydrogen bonds with the backbone more readily in vacuum, which disrupts the helix. Distribution functions of the spatial and angular position of water molecules in the proximity of the polypeptide backbone polar groups reveal the stabilization of the coiled structures by hydration. The transition from helix to coil is characterized by the appearance of a new peak in the probability distribution at a specific location characteristic of hydrogen bond formation between water and backbone polar groups. No significant insertion of water molecules is observed at the precise onset of unwinding, while (i, i + 3) hydrogen bond formation is frequently detected at the initiation of α-helix unwinding.