Journal of the American Chemical Society, Vol.125, No.21, 6573-6580, 2003
Non-arrhenius behavior in the unfolding of a short, hydrophobic alpha-helix. Complementarity of molecular dynamics and lattice model simulations
The unfolding of the last, C-terminal residue of AcNH2-((L)-Leu)(11)-NHMe in its a-helical form has been investigated by measuring the variation of free energy involved in the alpha(R) to beta conformational transition. These calculations were performed using large-scale molecular dynamics simulations in conjunction with the umbrella sampling method. For different temperatures ranging from 280 to 370 K, the free energy of activation was estimated. Concurrently, unfolding simulations of a homopolypeptide formed by twelve hydrophobic residues were carried out, employing a three-dimensional lattice model description of the peptide, with a temperature-dependent interaction potential. Using a Monte Carlo approach, the lowest free energy conformation, an analogue of a right-handed alpha-helix, was determined in the region where the peptide chain is well ordered. The free energy barrier separating this state from a distinct, compact conformation, analogue to a beta-strand, was determined over a large enough range of temperatures. The results of these molecular dynamics and lattice model simulations are consistent and indicate that the kinetics of the unfolding of a hydrophobic peptide exhibits a non-Arrhenius behavior closely related to the temperature dependence of the hydrophobic effect. These results further illuminate the necessity to include a temperature dependence in potential energy functions designed for coarse-grained models of proteins.