Evaluating the Conformations and Dynamics of Peptoid Macrocycles
Evaluating the Conformations and Dynamics of Peptoid Macrocycles
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DOI：
10.1021/acs.jpcb.2c01669
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发表时间：
2022-07-12
影响因子：
3.3
通讯作者：
Renfrew, P. Douglas
中科院分区：
文献类型：
--
作者：
Eastwood, James R. B.;Jiang, Linhai;Renfrew, P. Douglas
类肽大环化合物是多功能的和化学上不同的拟肽低聚物。然而，这些大环的构象和动力学尚未得到全面的评价，需要广泛的进一步调查。最近的研究表明，两个自由度，和四个不同的构象，充分描述每个单体骨架单元的行为，在大多数类肽寡聚体。在此基础上，我们进行了分子动力学模拟模型大环使用一套详尽的理想化可能的起始构象。模拟各种大小的类肽大环化合物产生了一组有限的人口构象。除了再现所有相关的实验确定的构象，模拟准确地预测了环八聚体构象，我们现在提出的第一个实验观察。三个相邻的二面角（φ（v）psi（v）ω（i+1））集表现出相关的曲轴运动的模拟过程中的类肽大环的六个残基和更大。这些相关的运动可能会发生在一个酰胺键的反转和协调旋转的前面的phi和psi的角度，他们的镜像构象的形式，在聚合物和肽研究的“曲轴翻转”运动的变化。这些类肽大环的能量景观可以被描述为通过个别曲轴翻转的变换而互连的构象网络。对于多达八个残基的大环，我们的景观映射基本上是完整的。
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 macrocydes 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 (phi(v) psi(v) omega(i+1)) 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 phi and psi 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.