title: The folding mechanism of collagen-like model peptides explored through detailed molecular simulations.
abstract: Collagen has a unique folding mechanism that begins with the formation of a triple-helical structure near its C terminus followed by propagation of this structure to the N terminus. To elucidate factors that affect the folding of collagen, we explored the folding pathway of collagen-like model peptides using detailed molecular simulations with explicit solvent. Using biased molecular dynamics we examined the latter stages of folding of a peptide model of native collagen, (Pro-Hyp-Gly)10, and a peptide that models a Gly --> Ser mutation found in several forms of osteogenesis imperfecta, (Pro-Hyp-Gly)3-Pro-Hyp-Ser-(Pro-Hyp-Gly)6. Starting from an unfolded state that contains a C-terminal nucleated trimer, (Pro-Hyp-Gly)10 folds to a structure where two of the three chains associate through water-mediated hydrogen bonds and the third is relatively separated from this dimer. Calculated free-energy profiles for folding from this intermediate to the final triple-helical structure suggest that further folding occurs at a rate of approximately one Pro-Hyp-Gly triplet per msec. In contrast, after 6 nsec of biased dynamics, the region N-terminal to the Ser residue in (Pro-Hyp-Gly)3-Pro-Hyp-Ser-(Pro-Hyp-Gly)6 folds to a structure where the three chains form close contacts near the N terminus, away from the mutation site. Further folding to an ideal triple-helical structure at the site of the mutation is unfavorable as the free energy of a triple-helical conformation at this position is more than 20 kcal/mol higher than that of a structure with unassociated chains. These data provide insights into the folding pathway of native collagen and the events underlying the formation of misfolded structures.
authors.affiliation: Department of Electrical Engineering, Massachusetts Institute of Technology, Massachusetts 02319, USA. cmstultz@mit.edu
authors.forename: Collin M
authors.initials: CM
authors.lastname: Stultz
mesh_terms: D000595:Amino Acid Sequence; D002942:Circular Dichroism; D003094:Collagen / Q000737:chemistry*; D003198:Computer Simulation; D006860:Hydrogen Bonding; D008954:Models, Biological; D008958:Models, Molecular; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D010446:Peptide Fragments; D010455:Peptides; D003094:Collagen