Molecular dynamics (MD) simulations have been used to characterize the effects of backbone N-amination of residues in a model β-hairpin peptide. This modification is of considerable interest as N-aminated peptides have been shown to inhibit amyloid-type aggregation. Six derivatives of the β-hairpin peptide, which contain one, two, or four N-aminated residues, have been studied. For each peptide 100 ns MD simulations starting from the folded β-hairpin structure were performed. The effects of the N-amination prove to be very sequence dependent. N-Amination of a residue involved in interstrand hydrogen bonding (Val3) leads to unfolding of the β-hairpin, whereas N-amination of a residue toward the C-terminus (Leu11) gives fraying at the termini of the peptide. In the other derivatives the peptide remains folded, with increasing levels of N-amination reducing the right-handed twist of the β-hairpin and favoring population of a type II′ rather than a type I′ β-turn. MD simulations (100 ns) have also been run for each peptide starting from an unfolded extended chain. Here, the peptide with four N-aminated residues shows the most folding into the β-hairpin (34%). Analysis of the simulations shows that N-amination favors the population of β (φ, ψ) conformations by the preceding residue due to, at least in part, a network of weak NH₂(i)–CO(i) and NH₂(i)–CO(i–2) hydrogen bonds. It also leads to a reduction of misfolding because of changes in the hydrogen-bonding potential. Both of these features help funnel the peptide to the folded β-hairpin structure. The conformational insights provided through this work give a firm foundation for the design of N-aminated peptide inhibitors for modulating protein–protein interactions and aggregation.

中文翻译：

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主链 N-氨基化通过氢键网络促进 β-发夹肽的折叠

分子动力学 (MD) 模拟已用于表征模型 β-发夹肽中残基的骨架 N-胺化作用。这种修饰具有相当大的意义，因为已证明 N-胺化肽可抑制淀粉样蛋白型聚集。已经研究了 β-发夹肽的六种衍生物，它们含有一个、两个或四个 N-氨基化残基。对于每个肽，从折叠的 β-发夹结构开始进行 100 ns MD 模拟。N-胺化作用证明是非常依赖于序列的。参与链间氢键 (Val3) 的残基的 N-氨基化导致 β-发夹的展开，而朝向 C-末端 (Leu11) 的残基的 N-氨基化在肽的末端产生磨损。在其他衍生物中，肽保持折叠状态，随着 N-胺化水平的增加，减少了 β-发夹的右手扭曲，并有利于 II' 型而不是 I' 型 β-转角。MD 模拟 (100 ns) 也已从展开的延伸链开始对每个肽运行。此处，具有四个 N-氨基化残基的肽折叠到 β-发夹中的次数最多 (34%)。模拟分析表明，N-氨基化有利于前面残基的 β (φ, ψ) 构象群，至少部分是由于弱 NH 网络₂ ( i )–CO( i ) 和NH ₂ ( i )–CO( i –2) 氢键。由于氢键电位的变化，它还导致错误折叠的减少。这两个特征都有助于将肽汇集到折叠的 β-发夹结构中。通过这项工作提供的构象见解为设计用于调节蛋白质-蛋白质相互作用和聚集的 N-胺化肽抑制剂奠定了坚实的基础。