Coarse-Grained Model of Coil-to-Helix Kinetics Demonstrates the Importance of Multiple Nucleation Sites in Helix Folding

An extension of a coarse-grained, implicit-solvent peptide model wherein each amino acid residue is represented by four interaction sites is presented and discussed. The model is used to study the coil-to-helix transition of five peptide sequences, ranging from all hydrophobic to all hydrophilic, for a 10-residue peptide. The thermodynamics of the folding transition are analyzed and discussed for each sequence, and the stability of the α-helix is correlated with the hydrophobic content of the sequence. In addition, for each sequence, the folding kinetics of the transition from random coil to full α-helix are analyzed, and the mean folding time is determined. Folding times vary from 59 ns for the most hydrophobic sequence to 132 ns for the most hydrophilic sequence. These folding times compare very well with those measured in experments. All sequences show single-exponential kinetics. A plot of the mean folding time versus the reciprocal of the Zimm-Bragg parameter σ [Formula: see text] a measure of the free energy cost of nucleating a helix [Formula: see text] is shown to be nonlinear, in contrast to the predictions of many theories of the coil-to-helix transition. It is proposed that the origin of this nonlinearity is due to multiple helix nucleation sites, indicating that even for short peptides such as those studied here, multiple folding pathways play an important role in the transition from random coil to native state.