Diversity of Secondary Structure in Catalytic Peptides with β-Turn-Biased Sequences.
Diversity of Secondary Structure in Catalytic Peptides with β-Turn-Biased Sequences.
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DOI：
10.1021/jacs.6b11348
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发表时间：
2017-01-11
影响因子：
15
通讯作者：
Miller SJ
中科院分区：
文献类型：
--
作者：
Metrano AJ;Abascal NC;Mercado BQ;Paulson EK;Hurtley AE;Miller SJ
X射线晶体学已被应用到一系列的四肽，以前评估的催化活性在atroposelective溴化反应的结构分析。该系列的共同点是中心Pro-Xaa序列，其中Pro是l-或d-脯氨酸，其被选择以有利于典型β-转角二级结构的成核。35个不同的肽序列的晶体学分析揭示了一系列的构象状态。所观察到的差异不仅出现在Pro-Xaa环区域被改变的情况下，而且还出现在引入侧翼残基的看似细微的改变时。在许多情况下，观察到相同序列的不同构象异构体，无论是作为同一晶胞内的非线性分子还是作为多晶型物。使用DFT的计算研究为固态结构特征的分析提供了额外的见解。选择X射线晶体结构进行了比较，从测量的质子化学位移，3 J值，和1H-1H-NOESY接触相应的解决方案的结构。这些发现意味着简单肽基催化剂的构象空间比以前可能暗示的更多样化。这个家庭的肽的多个基态构象的直接观察，以及与构象平衡相关联的动态过程，强调不仅是设计基于肽的催化剂的挑战，但也难以预测其可访问的过渡态。这些发现暗示了肽基催化剂的构象之间的低屏障相互转化的优点，用于多步，对映选择性反应。
X-ray crystallography has been applied to the structural analysis of a series of tetrapeptides that were previously assessed for catalytic activity in an atroposelective bromination reaction. Common to the series is a central Pro-Xaa sequence, where Pro is either l- or d-proline, which was chosen to favor nucleation of canonical β-turn secondary structures. Crystallographic analysis of 35 different peptide sequences revealed a range of conformational states. The observed differences appear not only in cases where the Pro-Xaa loop-region is altered, but also when seemingly subtle alterations to the flanking residues are introduced. In many instances, distinct conformers of the same sequence were observed, either as symmetry-independent molecules within the same unit cell or as polymorphs. Computational studies using DFT provided additional insight into the analysis of solid-state structural features. Select X-ray crystal structures were compared to the corresponding solution structures derived from measured proton chemical shifts, 3J-values, and 1H–1H-NOESY contacts. These findings imply that the conformational space available to simple peptide-based catalysts is more diverse than precedent might suggest. The direct observation of multiple ground state conformations for peptides of this family, as well as the dynamic processes associated with conformational equilibria, underscore not only the challenge of designing peptide-based catalysts, but also the difficulty in predicting their accessible transition states. These findings implicate the advantages of low-barrier interconversions between conformations of peptide-based catalysts for multistep, enantioselective reactions.