Stacked Fluoroaromatics as Supramolecular Synthons for Programming Protein Dimerization Specificity
Stacked Fluoroaromatics as Supramolecular Synthons for Programming Protein Dimerization Specificity
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DOI：
10.1002/anie.201105857
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Gao, Jianmin
中科院分区：
文献类型：
--
作者：
Pace, Christopher J.;Zheng, Hong;Gao, Jianmin
直接分子缔合的超分子合成子对于设计自组装材料和与生物系统相互作用的折叠体是非常可取的。[1]除了少数例外，蛋白质和多肽设计领域的许多工作利用极性基团作为超分子合成子，通过氢键和盐桥形成提供结构特异性。[1E]虽然芳香相互作用在蛋白质结构中普遍存在，但[2]芳香相互作用在蛋白质设计中很少使用，[3]可能是因为对它们相互作用的能量学了解不完全。芳香族残基主要被认为是疏水的，但它们参与了静电相互作用。[4]一个众所周知的例子是阳离子-π相互作用，它被许多信号蛋白所利用，例如乙酰胆碱受体和识别甲基化的组蛋白的色域。[5]两个堆积的芳环也可以通过静电机制相互作用，通常被称为π-π相互作用或四极相互作用。[6]我们小组最近的工作描述了堆积的苯基和全氟苯基对决定了螺旋束蛋白的二聚化专一性，从而显示了堆积的芳烃在水介质中作为超分子合成子的潜力。我们通过在模型蛋白质α2D中引入不同的堆积芳香族对，系统地研究了芳香族堆积能级。[8]结果显示，偶极-偶极和偶极诱导-偶极相互作用对芳香堆积的贡献令人惊讶地大。我们进一步证明，堆积的芳香族对有效地提供了高度相似的多肽单体的自分类，从而得到特定的二聚体物种。α2D是由DeGrado及其同事报道的一种从头设计的蛋白质。[8]这种35个残基的多肽折叠成一个二聚体螺旋束，并表现出高度合作和可逆的折叠行为，这使得它很容易表征其折叠和二聚的热力学。[9]α2D的一个显著特征是芳香族核心，它由两个苯丙氨酸对堆积在面对面的几何结构中(图1a)。这种独特的芳香族核心为研究芳香族堆积相互作用的能量学提供了一个理想的系统。在这项研究中，我们主要使用苯丙氨酸的氟化类似物，因为氢-氟取代引起的空间扰动最小。尽管在空间上保守，氟化可以引入相当大的扰动
Supramolecular synthons that direct molecular associations are highly desirable for the design of self-assembled materials and foldamers that interact with biological systems.[1] With a few exceptions, much work in the areas of protein and peptide design utilizes polar groups as supramolecular synthons that afford structural specificity through hydrogen bonding and salt-bridge formation.[1e] Although prevalent in protein structures,[2] aromatic interactions have been rarely utilized in protein design,[3] presumably owing to the incomplete understanding of their interaction energetics. The aromatic residues are primarily considered to be hydrophobic, yet they are known to engage in electrostatic interactions.[4] One wellknown example is the cation–π interaction, which is employed by numerous signaling proteins, such as acetylcholine receptors and chromodomains that recognize methylated histones.[5] Two stacked aromatic rings may also interact with each other through electrostatic mechanisms, often referred to as π–π interactions or quadrupole interactions.[6] Recent work from our group describes that a stacked phenyl and perfluorophenyl pair dictates the dimerization specificity of a helix-bundle protein, thereby showcasing the potential of stacked aromatics as supramolecular synthons in aqueous media.[7] Herein, we systematically examine the aromatic stacking energetics by introducing various stacked aromatic pairs into the model protein α2D.[8] The results reveal a surprisingly large contribution of dipole–dipole and dipole–induced-dipole interactions to aromatic stacking. We further demonstrate that the stacked aromatic pairs effectively afford self-sorting of highly analogous peptide monomers to give specific dimeric species. α2D is a de novo designed protein reported by DeGrado and co-workers.[8] This 35-residue polypeptide folds into a dimeric helix bundle and displays a highly cooperative and reversible folding behavior, which makes it easy to characterize the thermodynamics of its folding and dimerization.[9] A prominent feature of α2D is the aromatic core, which consists of two phenylalanine pairs stacking in the face-to-face geometry (Figure 1a). This unique aromatic core presents an ideal system for investigating the energetics of aromatic stacking interactions. We primarily used the fluorinated analogues of phenylalanine in this study because of the minimal steric perturbation caused by the hydrogen-tofluorine substitutions. Although sterically conservative, fluorination can introduce rather large perturbations to the