Chemistry Department, New York University, New York, NY 10003, USA.
Org Biomol Chem. 2020 Mar 25;18(12):2312-2320. doi: 10.1039/d0ob00453g.
We report a general approach to promote the folding of synthetic oligopeptides capable of forming homodimeric coiled coil assemblies. By pre-organizing the peptides on macrocyclic oligomer scaffolds, the stability of the coiled coils is enhanced with an observed increase in the melting temperature of 30 °C to 40 °C. Molecular dynamics simulations substantiate the hypothesis that the enhanced stability is established by constraining motion at the peptide termini and by pre-organizing intramolecular helix-helix contacts. We demonstrate the modularity of this approach by using a family of peptoid scaffolds to promote the folding of a dimeric coiled coil. Importantly, this strategy for templating coiled coils allows preservation of native amino acid sequences. Comparing a macrocyclic peptoid scaffold to its linear counterparts indicates that both types of assemblies are effective for organizing stable coiled coils. These results will guide future designs of coiled coil peptides for biomedical applications and as building blocks for more complex supramolecular assemblies.
我们报告了一种促进能够形成同二聚体卷曲螺旋组装的合成寡肽折叠的通用方法。通过将肽预组织在大环寡聚物支架上，可以增强卷曲螺旋的稳定性，观察到其熔点升高 30°C 至 40°C。分子动力学模拟证实了这样的假设，即通过限制肽末端的运动和预组织分子内螺旋-螺旋接触来建立增强的稳定性。我们通过使用一系列肽类似物支架来促进二聚体卷曲螺旋的折叠来证明这种方法的模块性。重要的是，这种模板卷曲螺旋的策略允许保留天然氨基酸序列。将大环肽类似物支架与其线性对应物进行比较表明，这两种类型的组装都可有效地组织稳定的卷曲螺旋。这些结果将指导未来用于生物医学应用的卷曲螺旋肽的设计，以及作为更复杂的超分子组装的构建块。
