Flexibility and cell permeability of cyclic Ras-inhibitor peptides revealed by coupled Nose Hoover equation
Flexibility and cell permeability of cyclic Ras-inhibitor peptides revealed by coupled Nose Hoover equation
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耦合 Nose Hoover 方程揭示了环状 Ras 抑制肽的灵活性和细胞通透性
DOI：
10.1021/acs.jcim.0c01427
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发表时间：
2021
影响因子：
5.6
通讯作者：
Yoshifumi Fukunishi and Ikuo Fukuda
中科院分区：
文献类型：
--
作者：
Kei Moritsugu;Koh Takeuchi;Narutoshi Kamiya;Junichi Higo;Isao Yasumatsu;Yoshifumi Fukunishi and Ikuo Fukuda
定量环肽的细胞渗透性对于它们的合理药物设计至关重要。然而，原因仍然不清楚为什么一个微小的化学修饰，如Ras抑制剂cyclorasin 9A 5和9A 54之间的差异，可以大大改变肽的渗透性。为了解决这个问题，我们使用我们最近开发的耦合Nose <$-Hoover方程（cNH）对这两种11-mer肽进行了增强的采样模拟。目前的cNH模拟实现了温度波动在很宽的范围内（240-600 K）在一个动态的方式，允许结构采样，以及核Overhauser效应测量验证。衍生的结构系综进行了全面的分析，通过全原子结构聚类，映射到主成分（PC），表征环状结构的衍生集群，并计算集群相关的几何和化学性质。在水溶液中，由于在主链环中包含Trp侧链，平面开放构象占主导地位，而紧凑闭合构象由于其紧凑性和高极性而有利于细胞渗透，也是可接近的。在一种衍生的PC中观察到构象依赖性细胞渗透性，表明9A 54中细胞渗透性降低是由于分离两种构象的高自由能势垒。自由能表面变化的起源被确定为改性残基2-3中柔性的损失，这是由于其侧链的体积增加。细胞渗透性的衍生分子机制突出了完整的结构动力学调查的意义，加速药物开发与环肽。
Quantifying the cell permeability of cyclic peptides is crucial for their rational drug design. However, the reasons remain unclear why a minor chemical modification, such as the difference between Ras inhibitors cyclorasin 9A5 and 9A54, can substantially change a peptide’s permeability. To address this question, we performed enhanced sampling simulations of these two 11-mer peptides using the coupled Nosé–Hoover equation (cNH) we recently developed. The present cNH simulations realized temperature fluctuations over a wide range (240–600 K) in a dynamic manner, allowing structural samplings that were well validated by nuclear Overhauser effect measurements. The derived structural ensembles were comprehensively analyzed by all-atom structural clustering, mapping the derived clusters onto principal components (PCs) that characterize the cyclic structure, and calculating cluster-dependent geometric and chemical properties. The planar-open conformation was dominant in aqueous solvent, owing to inclusion of the Trp side chain in the main-chain ring, while the compact-closed conformation, which favors cell permeation due to its compactness and high polarity, was also accessible. Conformation-dependent cell permeability was observed in one of the derived PCs, demonstrating that decreased cell permeability in 9A54 is due to the high free energy barrier separating the two conformations. The origin of the change in free energy surface was determined to be loss of flexibility in the modified residues 2–3, resulting from the increased bulkiness of their side chains. The derived molecular mechanism of cell permeability highlights the significance of complete structural dynamics surveys for accelerating drug development with cyclic peptides.