Hoang Huy N, Hill Timothy A, Ruiz-Gómez Gloria, Diness Frederik, Mason Jody M, Wu Chongyang, Abbenante Giovanni, Shepherd Nicholas E, Fairlie David P
Australian Research Council Centre of Excellence in Advanced Molecular Imaging , Institute for Molecular Bioscience , The University of Queensland , Brisbane , QLD 4072 , Australia . Email:
Structural Bioinformatics , BIOTEC , Technische Universität Dresden , Tatzberg 47-51 , 01307 Dresden , Germany.
Chem Sci. 2019 Oct 3;10(45):10595-10600. doi: 10.1039/c9sc04153b. eCollection 2019 Dec 7.
Protein-protein interactions involve hotspots as small as 4 sequential amino acids. Corresponding tetrapeptides have no structure in water. Here we report linking side chains of amino acids X and Z to form 24 cyclic tetrapeptides, cyclo-[XAAZ]-NH, and stabilise 14-18 membered rings that mimic different kinds of non-regular secondary structures found in protein hotspots. 2D NMR spectra allowed determination of 3D structures for 14 cyclic tetrapeptides in water. Five formed two (, + 3) hydrogen bonds and a beta/gamma (, ) or beta (, , ) turn; eight formed one (, + 4) hydrogen bond and twisted into a non-helical (, , , , ) or helical (, , ) alpha turn; one was less structured (). A beta or gamma turn was favoured for Z = Dab, Orn or Glu due to a 1 (+) rotamer, while an alpha turn was favoured for Z = Dap (but not X = Dap) due to a (-) rotamer. Surprisingly, an unstructured peptide ARLARLARL could be twisted into a helix when either a helical or non-helical alpha turn (, , , , ) with Z = Dap was attached to the N-terminus. These structural models provide insights into stability for different turns and twists corresponding to non-regular folds in protein hotspots.
蛋白质-蛋白质相互作用涉及小至4个连续氨基酸的热点区域。相应的四肽在水中没有结构。在此，我们报告将氨基酸X和Z的侧链连接起来，形成24种环四肽，环-[XAAZ]-NH，并稳定14至18元环，这些环模拟了在蛋白质热点区域发现的不同类型的非规则二级结构。二维核磁共振光谱可确定水中14种环四肽的三维结构。其中五种形成了两个（，+3）氢键以及一个β/γ（，）或β（，，）转角；八种形成了一个（，+4）氢键，并扭曲成非螺旋（，，，，）或螺旋（，，）α转角；一种结构较少（）。当Z = Dab、Orn或Glu时，由于存在1（+）旋转异构体，β或γ转角更受青睐；而当Z = Dap（但X = Dap时除外）时，由于存在（-）旋转异构体，α转角更受青睐。令人惊讶的是，当将具有Z = Dap的螺旋或非螺旋α转角（，，，，）连接到N端时，无结构的肽ARLARLARL可以扭曲成螺旋结构。这些结构模型为蛋白质热点区域中与非规则折叠相对应的不同转角和扭曲的稳定性提供了见解。
