The most abundant natural collagens form heterotrimeric triple helices. Synthetic mimics of collagen heterotrimers have been found to fold slowly, even compared to the already slow rates of homotrimeric helices. These prolonged folding rates are not understood. Here we compare the stabilities, specificities and folding rates of three heterotrimeric collagen mimics designed through a computationally assisted approach. The crystal structure of one ABC-type heterotrimer verified a well-controlled composition and register and elucidated the geometry of pairwise cation–π and axial and lateral salt bridges in the assembly. This collagen heterotrimer folds much faster (hours versus days) than comparable, well-designed systems. Circular dichroism and NMR data suggest the folding is frustrated by unproductive, competing heterotrimer species and these species must unwind before refolding into the thermodynamically favoured assembly. The heterotrimeric collagen folding rate is inhibited by the introduction of preformed competing triple-helical assemblies, which suggests that slow heterotrimer folding kinetics are dominated by the frustration of the energy landscape caused by competing triple helices.

最丰富的天然胶原蛋白形成异源三聚体三螺旋。人们发现胶原蛋白异源三聚体的合成模拟物折叠速度很慢，甚至与已经很慢的同源三聚体螺旋相比也是如此。这些延长的折叠率尚不清楚。在这里，我们比较了通过计算辅助方法设计的三种异源三聚体胶原模拟物的稳定性、特异性和折叠率。一种 ABC 型异源三聚体的晶体结构验证了良好控制的组成和记录，并阐明了组装中成对阳离子 - π以及轴向和横向盐桥的几何形状。这种胶原蛋白异源三聚体的折叠速度比同类的精心设计的系统要快得多（几小时与几天）。圆二色性和核磁共振数据表明，折叠受到非生产性、竞争性异三聚体物种的阻碍，并且这些物种必须在重新折叠成热力学有利的组装之前解旋。异源三聚体胶原折叠速率通过引入预形成的竞争性三螺旋组件而受到抑制，这表明缓慢的异源三聚体折叠动力学主要是由竞争三螺旋引起的能量景观的挫败所主导。