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: Collin M Stultz
• Journal: Protein science : a publication of the Protein Society (Protein Sci) Vol. 15 Issue 9 Pg. 2166-77 (Sep 2006) ISSN: 0961-8368 [Print] United States
• PMID: 16943446 (Publication Type: Journal Article)

Chemical References

• Peptide Fragments
• Peptides
• Collagen

Topics

• Amino Acid Sequence
• Circular Dichroism
• Collagen (chemistry)
• Computer Simulation
• Hydrogen Bonding
• Models, Biological
• Models, Molecular
• Models, Theoretical
• Molecular Sequence Data
• Nuclear Magnetic Resonance, Biomolecular
• Peptide Fragments (chemistry)
• Peptides
• Protein Folding
• Protein Structure, Secondary