Wang Jia, McElheny Dan, Fu Yanwen, Li Guangyu, Kim Joohyun, Zhou Zhe, Wu Ling, Keiderling Timothy A, Hammer Robert P
Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803-1804, USA.
Biopolymers. 2009;92(5):452-64. doi: 10.1002/bip.21258.
C(alpha,alpha)-disubstituted amino acids (alphaalphaAAs) are widely used to conformationally constrain peptides. A series of pentapeptides containing dipropylglycine (Dpg) at alternating positions and their alpha-amino acid counterpart L-norvaline (Nva) analogues were synthesized to fully investigate the impact of Dpg on peptide backbone structure in aqueous solution. CD, VCD, and NMR spectral analysis suggest that Dpg containing peptides adopt more ordered structures relative to their Nva containing analogues. The central residues (Ala, Thr, Tyr, Val) and the charged side-chains of Glu and Lys play important roles in the degree of peptide folding. Hydrophobic and branched residues (Val, Tyr) at the central position of the peptide produce greater folding as judged by CD and NMR. Variation of the chemical shift with temperature (Deltadelta/DeltaT NH) of Ac-Glu-Dpg-Tyr-Dpg-Lys-NH(2) suggests a series of i --> i + 3 hydrogen bonds between the N-terminal acetyl carbonyl and the Tyr(3) NH, and the Glu(1) carbonyl and the Dpg(4) NH. The solution conformation of Ac-Glu-Dpg-Tyr-Dpg-Lys-NH(2) calculated from NMR-derived constraints shows a 3(10)-helical structure (two repetitive type-III beta-turns) at residues 1-4, which is supported by 2D NMR, CD, and VCD spectra. Analysis of NMR-derived models of these peptides suggest that there is a strong hydrophobic interaction of the pro-S propyl side chain of Dpg(2) and the Tyr(3) side-chain that may be a strong stabilizing force of the peptide folding in water.
C(α,α)-二取代氨基酸（ααAAs）被广泛用于肽的构象约束。合成了一系列在交替位置含有二丙基甘氨酸（Dpg）及其α-氨基酸对应物L-正缬氨酸（Nva）类似物的五肽，以全面研究Dpg对水溶液中肽主链结构的影响。圆二色光谱（CD）、振动圆二色光谱（VCD）和核磁共振光谱（NMR）分析表明，含Dpg的肽相对于其含Nva的类似物采用更有序的结构。中心残基（丙氨酸、苏氨酸、酪氨酸、缬氨酸）以及谷氨酸和赖氨酸的带电侧链在肽折叠程度中起重要作用。根据CD和NMR判断，肽中心位置的疏水和支链残基（缬氨酸、酪氨酸）产生更大的折叠。Ac-Glu-Dpg-Tyr-Dpg-Lys-NH₂的化学位移随温度的变化（Δδ/ΔT NH）表明，在N端乙酰羰基与Tyr(3) NH以及Glu(1)羰基与Dpg(4) NH之间存在一系列i→i + 3氢键。根据NMR衍生约束计算得到的Ac-Glu-Dpg-Tyr-Dpg-Lys-NH₂的溶液构象在残基1-4处显示出3(10)-螺旋结构（两个重复的III型β-转角），这得到了二维NMR、CD和VCD光谱的支持。对这些肽的NMR衍生模型的分析表明，Dpg(2)的前手性丙基侧链与Tyr(3)侧链之间存在强烈的疏水相互作用，这可能是肽在水中折叠的强大稳定力。
