omega-amino acids in peptide design. Crystal structures and solution conformations of peptide helices containing a beta-alanyl-gamma-aminobutyryl segment
omega-amino acids in peptide design. Crystal structures and solution conformations of peptide helices containing a beta-alanyl-gamma-aminobutyryl segment
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DOI：
10.1021/ja970566w
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发表时间：
1997-10-01
影响因子：
15
通讯作者：
Balaram, P
中科院分区：
文献类型：
--
作者：
Karle, IL;Pramanik, A;Balaram, P
在肽序列中插入非手性ω -氨基酸导致可剪切的肽键被蛋白水解稳定的C-C键取代。这提供了一种创造肽模拟物的方便方法。本研究确定了八肽和非肽的螺旋结构的保存，其序列中有中心位置的p -和-氨基酸。单晶的x射线衍射分析和核磁共振研究已经被用来研究通过使用β -ala - γ - abu段（β -ala = β -丙氨酸，γ - abu = γ -氨基丁酸）在骨架中引入（- ch2 -）(n)基团对规则的3(10)-或α -螺旋的扰动程度，β -ala - γ - abu段（β -ala = β -丙氨酸，γ - abu = γ -氨基丁酸），其形式与（Gly）3段同态。在晶体中，八肽boc - leu - aib - val - β - ala -gamma- abu - leu - aib - val - β - ala -gamma- abu - leu - aib - val - ala - leu - aib - val - ala - leu - aib - ome(2)保留了它们的螺旋基序，并有轻微的凸起。五种新型的4—>1、5—>1和6—>1氢键环由多达3个额外的CH2基团形成。肽1的细胞参数为P2(1)2(1)2(1)空间群，a=11.506(1)埃，b=16.600(1)埃，c=27.362(1)埃，R=6.1%，对2696个测量数据>4 sigma(F)；对于未胜肽2，空间群为P2(1), a=8.605(3)埃，b=22.806(4)埃，c=19.014(3)埃，β =101.47(2)度，R=7.5%，测量了3797个数据>4 sigma(F)。从CDCl3的核磁共振研究中可以看出，肽2在溶液中也保持螺旋构象，这表明位于中心的柔性β - ala - γ - abu段可以舒适地容纳成螺旋结构，采用聚（亚甲基）单元的特定C-C键的间扭构象。使用核磁共振导出的约束条件进行核磁共振模拟生成的20个主结构构象的结构与低RMSD值（0.78 +/- 0.05埃）重叠，进一步表明在这些肽中β - ala - γ - abu段的构象灵活性有限，并且主要局限于螺旋构象。
Insertion of achiral omega-amino acids into peptide sequences results in replacement of scissile peptide bonds by proteolytically stable C-C bonds. This provides a convenient means of creating peptidomimetics. The present study establishes the preservation of helical structures in octa-and undecapeptides with centrally located, P-and gamma-amino acids in the Sequence. X-ray diffraction analyses of single crystals and NMR studies have been used to investigate the extent of perturbations of a regular 3(10)- or alpha-helix by the introduction of (-CH2-)(n) groups into the backbone by the use of the beta-Ala-gamma-Abu segment (beta-Ala = beta-alanine, gamma-Abu = gamma-aminobutyric acid), which is formally homomorphous with a (Gly)3 segment. In crystals, the octapeptide Boc-Leu-Aib-Val-beta-Ala-gamma-Abu-Leu-Aib-Val-OMe (1) and the undecapeptide Boc-Leu-Aib-Val-beta-Ala-gamma-Abu-Leu-Aib-Val-Ala-Leu-Aib-OMe (2) retain their helical motifs with minor bulges. Five new types of 4-->1, 5-->1, and 6-->1 hydrogen bond rings are formed with up to three extra CH2 moieties. Cell parameters for peptide 1 are space group P2(1)2(1)2(1) with a=11.506 (1) Angstrom, b=16.600 (1) Angstrom, c=27.362(1) Angstrom, and R=6.1% for 2696 data measured >4 sigma(F); for the undecapeptide 2, the space group is P2(1) with a=8.605 (3) Angstrom, b=22.806 (4) Angstrom, c=19.014 (3) Angstrom, beta=101.47(2)degrees, and R=7.5% for 3797 data measured >4 sigma(F). Helical conformations in solution are also maintained for peptide 2 as is evident from NMR studies in CDCl3, which suggest that the centrally positioned, flexible beta-Ala-gamma-Abu segment can be comfortably accommodated into helical structures adopting gauche conformations about specific C-C bonds of the poly(methylene) units. Twenty structures for backbone conformations generated from MD simulations using NMR-derived contraints, superpose with a low RMSD value (0.78 +/- 0.05 Angstrom), further indicating that in these peptides the conformational flexibility of the beta-Ala-gamma-Abu segment is limited and confined to largely helical conformations.