Quantifying End-to-End Conformational Communication of Chirality through an Achiral Peptide Chain
Quantifying End-to-End Conformational Communication of Chirality through an Achiral Peptide Chain
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DOI：
10.1002/anie.200901892
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Morris, Gareth A.
中科院分区：
文献类型：
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作者：
Clayden, Jonathan;Castellanos, Alejandro;Morris, Gareth A.
螺旋性是肽的二级结构的普遍特征：由L-氨基酸构建的肽通常采用右旋螺旋结构，即使大部分链是非手性的。[1]螺旋肽基序可以通过掺入季氨基酸如Aib（氨基异丁酸）来稳定，[2]并且Aib的寡聚体采用外消旋螺旋构象。[3，4]手性单体沿着任何聚合物链的合理分布可以控制左旋或右旋螺旋的频繁采用。[5]偏向于一种绝对螺旋度也可能是由于末端手性残基共价[6，7]或非共价[8]结合到非手性肽链上。在极限情况下，绝对螺旋性（即左旋或右旋螺旋偏好）可以在构型上非手性的寡聚体中由单个末端氨基酸诱导。Toniolo等人的工作。(for短Aibn寡聚物）[6]和Inai et al. (for Aib-ΔZPhe（ΔZPhe=（Z）-二脱氢苯丙氨酸）[7，8]的寡聚体显示，末端手性残基的共价或非共价连接导致至少部分肽结构中的螺旋度偏好[9]，可通过圆二色性检测。我们现在确定的是，末端手性残基的不对称影响可以通过单个孤立的螺旋结构持续多久，换句话说，由非手性单体构建的螺旋肽可以在不断增加的距离上携带关于末端残基的信息的保真度。以前的研究已经使用CD检测作为一个整体的低聚物的螺旋度，但没有信息定位在螺旋末端的不对称性可以通过这种方法收集。[10]随着非手性单体的螺旋被延长，每个非手性残基必须携带有限的螺旋反转机会，导致生长低聚物末端的不对称环境的侵蚀。使用一个简单的光谱技术，我们现在已经评估了本地的不对称性的一对偕“记者”1H核在C末端的肽含有一个单一的N-末端手性残基，因此已经量化的距离，其中低聚物保留在溶液中的螺旋偏好和保真度，每个非手性氨基酸传输螺旋偏好沿着链。该方法依赖于通过NMR光谱法观察两个1H核之间的非等时性，除非它们发现自己处于手性环境中，否则这两个1H核是不可区分的。在完全由非手性单体构建的螺旋中，并且在NMR时间尺度上快速反转，两个“报告”核快速交换并且必须是等重的。[11]如果远程手性影响成功地诱导优先在寡聚体中的一个绝对螺旋，核的局部环境的对称性将被打破，呈现非对映异构核各向异性。如果手性控制器位于足够远的地方，以避免与报告核的直接相互作用，异时性的程度反映了两个假对映体环境的加权平均值，因此反映了一个绝对螺旋度超过另一个的局部过量。因此，将非等时性量化为这些核之间的化学位移差异，并观察其随着螺旋长度的增加而衰减，可以提供一种经验测量方法，来测量手性影响可以在肽中持续存在的距离。我们选择1-氨基异丁酸（Aib（1））作为构建螺旋的非手性单体氨基酸，因为众所周知，掺入Aib的低聚物可形成310螺旋结构[2-4]，其在室温下在NMR时间尺度上快速进行螺旋反转。[4]我们目标的大致结构是...
Helicity is a widespread characteristic of the secondary structure of peptides: those built of L-amino acids typically adopt right-handed helical structures, even when most of the chain is achiral.[1] Helical peptide motifs may be stabilized by the incorporation of quaternary amino acids such as Aib (aminoisobutyric acid),[2] and oligomers of Aib adopt racemic helical conformations.[3, 4] Favored adoption of a left-or righthanded helix may be controlled by judicious distribution of chiral monomers along any polymer chain.[5] A bias towards one absolute sense of helicity may also arise from a terminal chiral residue bound covalently [6, 7] or noncovalently [8] to an otherwise achiral peptide chain. At the limit, absolute helicity (that is, a left-or right-handed helical preference) may be induced in an otherwise configurationally achiral oligomer by a single terminal amino acid. The work of Toniolo et al.(for short Aibn oligomers)[6] and of Inai et al.(for oligomers of Aib-ΔZPhe (ΔZPhe=(Z)-didehydrophenylalanine)[7, 8] has shown that covalent or noncovalent attachment of a terminal chiral residue leads to a helicity preference [9] in at least part of the peptide structure, detectable by circular dichroism. What we now establish is how far the asymmetric influence of a terminal chiral residue can persist through a single isolated helical structure—in other words the fidelity with which a helical peptide built of achiral monomers can carry information about a terminal residue over ever increasing distances. Previous studies have used CD to detect helicity in the oligomer as a whole, but no information on asymmetry localized at the helix terminus can be gathered by this method.[10] As a helix of achiral monomers is lengthened, every achiral residue must carry a finite chance of helix inversion, leading to erosion of the asymmetric environment at the terminus of the growing oligomer. Using a simple spectroscopic technique, we have now evaluated the local asymmetry of a pair of geminal “reporter” 1H nuclei at the C terminus of a peptide containing a single N-terminal chiral residue, and hence have quantified both the distance over which oligomers retain a helical preference in solution and the fidelity with which each achiral amino acid transmits a helical preference along the chain. The method relies on the observation by NMR spectroscopy of anisochronicity between two 1H nuclei which are indistinguishable unless they find themselves in a chiral environment. In a helix built entirely of achiral monomers, and inverting rapidly on the NMR timescale, the two “reporter” nuclei are in fast exchange and must be isochronous.[11] If a remote chiral influence succeeds in inducing preferentially one absolute helicity in the oligomer, the symmetry of the local environment of the nuclei will be broken, rendering the diastereotopic nuclei anisochronous. Provided the chiral controller is located sufficiently far away to avoid direct interaction with the reporter nuclei, the degree of anisochronicity reflects a weighted average of two pseudoenantiomeric environments and therefore reflects the local excess of one absolute helicity over the other. Quantifying the anisochronicity as a chemical-shift difference between these nuclei, and observing its decay with increasing helix length, may thus provide an empirical measure of the distance over which a chiral influence can persist in a peptide. We chose 1-aminoisobutyric acid (Aib (1)) as the achiral monomeric amino acid from which to build the helix since oligomers incorporating Aib are well-known to form 310-helical structures [2–4] which undergo helix inversion rapidly on the NMR timescale at room temperature.[4] The generalized structure of our targets is …