Cyclic peptides: backbone rigidification and capability of mimicking motifs at protein-protein interfaces.
Cyclic peptides: backbone rigidification and capability of mimicking motifs at protein-protein interfaces.
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DOI：
10.1039/d0cp04633g
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发表时间：
2021-01-06
期刊：
影响因子：
--
通讯作者：
Lin YS
中科院分区：
文献类型：
--
作者：
Huang H ;Damjanovic J ;Miao J ;Lin YS
环化通常用于提高基于肽的探针和治疗剂的靶标结合亲和力。许多结构基序已在蛋白质-蛋白质界面上被识别，并为使用环肽的抑制剂设计提供了有希望的目标。通常认为环化肽相对于其线性对应物是刚性的。这种刚性化可能预先组织分子以与其目标正确相互作用。然而，目前人们对环化对肽构型熵等的实际影响的大小和分子水平起源知之甚少。此外，即使手头有数千个所需的结构基序，目前也无法先验地识别最有希望使用环肽进行模拟的结构基序，也无法选择理想的接头长度。相反，需要对各种环肽设计进行劳动密集型化学合成和实验表征，以期找到一种具有改善的靶亲和力的环肽。在此，利用聚甘氨酸的分子动力学模拟，我们阐明了头尾环化如何影响肽主链二面体熵，并开发了一种简单的策略来快速筛选可以被预组织环肽可靠模拟的结构。正如预期的那样，环化通常会导致主链二面体熵的减少；然而，值得注意的是，当聚甘氨酸的长度大于 9 个残基时，这种影响最小。我们还发现，小聚甘氨酸肽环化后主链二面体熵的减少并不是由于二面体的分布更受限制；而是由于二面体的分布更受限制。相反，正是特定二面体之间的相关性导致了环肽构型熵的降低。利用我们全面的环 Gn 结构整体，我们获得了环肽可接近的构象的整体图景。以最近在蛋白质-蛋白质界面上发现的“热环”为例，我们提供了明确的指南，用于选择模拟环肽的“最简单”热环，并确定适当的环肽长度。总之，我们的结果提供了对这类有趣分子的热力学和结构的理解。该信息对于设计蛋白质-蛋白质相互作用的环肽抑制剂特别有用。
Cyclization is commonly employed in efforts to improve the target binding affinity of peptide-based probes and therapeutics. Many structural motifs have been identified at protein–protein interfaces and provide promising targets for inhibitor design using cyclic peptides. Cyclized peptides are generally assumed to be rigidified relative to their linear counterparts. This rigidification potentially pre-organizes the molecules to interact properly with their targets. However, the actual impact of cyclization on, for example, peptide configurational entropy, is currently poorly understood in terms of both its magnitude and molecular-level origins. Moreover, even with thousands of desired structural motifs at hand, it is currently not possible to a priori identify the ones that are most promising to mimic using cyclic peptides nor to select the ideal linker length. Instead, labor-intensive chemical synthesis and experimental characterization of various cyclic peptide designs is required, in hopes of finding one with improved target affinity. Herein, using molecular dynamics simulations of polyglycines, we elucidated how head-to-tail cyclization impacts peptide backbone dihedral entropy and developed a simple strategy to rapidly screen for structures that can be reliably mimicked by preorganized cyclic peptides. As expected, cyclization generally led to a reduction in backbone dihedral entropy; notably, however, this effect was minimal when the length of polyglycines was >9 residues. We also found that the reduction in backbone dihedral entropy upon cyclization of small polyglycine peptides does not result from more restricted distributions of the dihedrals; rather, it was the correlations between specific dihedrals that caused the decrease in configurational entropy in the cyclic peptides. Using our comprehensive cyclo-Gn structural ensembles, we obtained a holistic picture of what conformations are accessible to cyclic peptides. Using “hot loops” recently identified at protein–protein interfaces as an example, we provide clear guidelines for choosing the “easiest” hot loops for cyclic peptides to mimic and for identifying appropriate cyclic peptide lengths. In conclusion, our results provide an understanding of the thermodynamics and structures of this interesting class of molecules. This information should prove particularly useful for designing cyclic peptide inhibitors of protein–protein interactions.
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