Influence of Lipidation on the Folding and Stability of Collagen Triple HelicesAn Experimental and Theoretical Study

The folding of triple-helical collagen,
the most abundant protein
in nature, relies on the nucleation and propagation along the strands.
Hydrophobic moieties are crucial for the folding and stability of
numerous proteins. Instead, nature uses for collagen a trimerization
domain and cis-trans prolyl isomerases
to facilitate and accelerate triple helix formation. Yet, pendant
hydrophobic moieties endow triple-helical collagen with hyperstability
and accelerate the cis-trans isomerization
to an extent that thermally induced unfolding and folding of collagen
triple helices take place at the same speed. Here, we systematically
explored the effect of pendant fatty acids on the folding and stability
of collagen triple helices. Thermal denaturation and kinetic studies
with a series of collagen mimetic peptides (CMPs) bearing saturated
and unsaturated fatty acids with different lengths revealed that longer
and more flexible fatty acid appendages increase the stability and
the folding rate of collagen triple helices. Molecular dynamics simulations
combined with experimental data indicate that the hydrophobic appendages
stabilize the triple helix by interaction with the grooves of the
collagen triple helix and accelerate the folding and unfolding process
by creating a molten globule-like intermediate.