Laboratory of Organic Chemistry, ETH Zurich, D-CHAB, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
Laboratory of Physical Chemistry, ETH Zurich, D-CHAB, Vladimir-Prelog-Weg 2, 8093 Zurich, Switzerland.
J Am Chem Soc. 2021 Apr 21;143(15):5937-5942. doi: 10.1021/jacs.1c01512. Epub 2021 Apr 8.
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 - prolyl isomerases to facilitate and accelerate triple helix formation. Yet, pendant hydrophobic moieties endow triple-helical collagen with hyperstability and accelerate the - 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.
三股螺旋胶原的折叠，是自然界中最丰富的蛋白质，依赖于链上的成核和扩展。疏水性部分对于许多蛋白质的折叠和稳定性至关重要。然而，大自然使用三聚体结构域和脯氨酰异构酶来促进和加速三螺旋的形成。然而，悬垂的疏水性部分赋予三螺旋胶原超稳定性，并加速 - 异构化，以至于胶原三螺旋的热诱导展开和折叠以相同的速度发生。在这里，我们系统地研究了悬垂脂肪酸对胶原三螺旋折叠和稳定性的影响。一系列带有饱和和不饱和脂肪酸的胶原模拟肽 (CMP) 的热变性和动力学研究表明，更长、更灵活的脂肪酸侧链增加了胶原三螺旋的稳定性和折叠速率。分子动力学模拟结合实验数据表明，疏水性侧链通过与胶原三螺旋的凹槽相互作用稳定三螺旋，并通过形成类似无规卷曲的中间体加速折叠和展开过程。
