Department of Chemistry, New York University, New York, New York 10003, United States.
Center for Data Science, New York University, New York, New York 10011, United States.
J Phys Chem B. 2022 Jul 21;126(28):5161-5174. doi: 10.1021/acs.jpcb.2c01669. Epub 2022 Jul 12.
Peptoid macrocycles are versatile and chemically diverse peptidomimetic oligomers. However, the conformations and dynamics of these macrocycles have not been evaluated comprehensively and require extensive further investigation. Recent studies indicate that two degrees of freedom, and four distinct conformations, adequately describe the behavior of each monomer backbone unit in most peptoid oligomers. On the basis of this insight, we conducted molecular dynamics simulations of model macrocycles using an exhaustive set of idealized possible starting conformations. Simulations of various sizes of peptoid macrocycles yielded a limited set of populated conformations. In addition to reproducing all relevant experimentally determined conformations, the simulations accurately predicted a cyclo-octamer conformation for which we now present the first experimental observation. Sets of three adjacent dihedral angles (ϕ, ψ, ω) exhibited correlated crankshaft motions over the course of simulation for peptoid macrocycles of six residues and larger. These correlated motions may occur in the form of an inversion of one amide bond and the concerted rotation of the preceding ϕ and ψ angles to their mirror-image conformation, a variation on "crankshaft flip" motions studied in polymers and peptides. The energy landscape of these peptoid macrocycles can be described as a network of conformations interconnected by transformations of individual crankshaft flips. For macrocycles of up to eight residues, our mapping of the landscape is essentially complete.
肽缩氨酸大环是多功能且化学结构多样的拟肽寡聚物。然而，这些大环的构象和动力学尚未得到全面评估，需要进行广泛的进一步研究。最近的研究表明，在大多数肽缩氨酸寡聚物中，两个自由度和四个不同的构象足以描述每个单体主链单元的行为。基于这一见解，我们使用一组详尽的理想化可能起始构象对模型大环进行了分子动力学模拟。对各种大小的肽缩氨酸大环的模拟产生了一组有限的占据构象。除了重现所有相关的实验确定构象外，模拟还准确地预测了环辛烷构象，我们现在提出了对此构象的第一个实验观察结果。对于具有六个残基及以上的肽缩氨酸大环，三个相邻的二面角（φ、ψ、ω）组在模拟过程中表现出相关的曲柄运动。这些相关的运动可能以一种酰胺键的反转和前φ和ψ角度的协同旋转到它们的镜像构象的形式发生，这是在聚合物和肽中研究的“曲柄翻转”运动的一种变体。这些肽缩氨酸大环的能量景观可以描述为通过单个曲柄翻转的变换相互连接的构象网络。对于多达八个残基的大环，我们对景观的映射基本上是完整的。
