Banerjee Raja, Sheet Tridip, Banerjee Srijan, Biondi Barbara, Formaggio Fernando, Toniolo Claudio, Peggion Cristina
Department of Chemical Sciences, University of Padova, 35131 Padova, Italy.
Institute of Biomolecular Chemistry, Padova Unit, CNR, 35131 Padova, Italy.
Biochemistry. 2021 Sep 14;60(36):2704-2714. doi: 10.1021/acs.biochem.1c00340. Epub 2021 Aug 31.
In synthetic peptides containing Gly and coded α-amino acids, one of the most common practices to enhance their helical extent is to incorporate a large number of l-Ala residues along with noncoded, strongly foldameric α-aminoisobutyric acid (Aib) units. Earlier studies have established that Aib-based peptides, with propensity for both the 3- and α-helices, have a tendency to form ordered three-dimensional structure that is much stronger than that exhibited by their l-Ala rich counterparts. However, the achiral nature of Aib induces an inherent, equal preference for the right- and left-handed helical conformations as found in Aib homopeptide stretches. This property poses challenges in the analysis of a model peptide helical conformation based on chirospectroscopic techniques like electronic circular dichroism (ECD), a very important tool for assigning secondary structures. To overcome such ambiguity, we have synthesized and investigated a thermally stable 14-mer peptide in which each of the Aib residues of our previously designed and reported analogue ABGY (where B stands for Aib) is replaced by C-methyl-l-valine (L-AMV). Analysis of the results described here from complementary ECD and H nuclear magnetic resonance spectroscopic techniques in a variety of environments firmly establishes that the L-AMV-containing peptide exhibits a significantly stronger preference compared to that of its Aib parent in terms of conferring α-helical character. Furthermore, being a chiral α-amino acid, L-AMV shows an intrinsic, extremely strong bias for a quite specific (right-handed) screw sense. These findings emphasize the relevance of L-AMV as a more appropriate unit for the design of right-handed α-helical peptide models that may be utilized as conformationally constrained scaffolds.
在含有甘氨酸和编码α-氨基酸的合成肽中，增强其螺旋程度最常见的做法之一是引入大量的L-丙氨酸残基以及非编码的、具有强折叠能力的α-氨基异丁酸（Aib）单元。早期研究表明，基于Aib的肽具有形成3-螺旋和α-螺旋的倾向，它们倾向于形成比富含L-丙氨酸的对应肽更强的有序三维结构。然而，Aib的非手性性质导致在Aib同肽片段中对右手和左手螺旋构象具有固有的、同等的偏好。这种性质给基于圆二色光谱（ECD）等手性光谱技术分析模型肽螺旋构象带来了挑战，而ECD是确定二级结构的非常重要的工具。为了克服这种模糊性，我们合成并研究了一种热稳定的14肽，其中我们之前设计并报道的类似物ABGY（其中B代表Aib）中的每个Aib残基都被C-甲基-L-缬氨酸（L-AMV）取代。通过在各种环境中互补的ECD和氢核磁共振光谱技术对这里描述的结果进行分析，有力地证实了与Aib母体肽相比，含L-AMV的肽在赋予α-螺旋特征方面表现出明显更强的偏好。此外，作为一种手性α-氨基酸，L-AMV对一种非常特定的（右手）螺旋方向表现出内在的、极强的偏向性。这些发现强调了L-AMV作为设计右手α-螺旋肽模型更合适单元的相关性，该模型可作为构象受限支架使用。
