Folding and misfolding of the collagen triple helix are studied through molecular dynamics simulations of two collagenlike peptides, [(POG) 10]3 and [(POG)4POA(POG)5] 3, which are models for wild-type and mutant collagen, respectively. To extract long time dynamics from short trajectories, we employ Markov state models. By analyzing thermodynamic and kinetic quantities calculated from the Markov state models, we examine folding mechanisms of the collagen triple helix and consequences of glycine mutations. We find that the C-to-N zipping of the collagen triple helix must be initiated by a nucleation event consisting of formation of three stable hydrogen bonds, and that zipping through a glycine mutation site requires a renucleation event which also consists of formation of three stable hydrogen bonds. Our results also suggest that slow kinetics, rather than free energy differences, is mainly responsible for the stability of the collagen triple helix. © 2007 by the Biophysical Society.
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