Bour Petr, Kim Joohyun, Kapitan Josef, Hammer Robert P, Huang Rong, Wu Ling, Keiderling Timothy A
Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
Chirality. 2008 Nov;20(10):1104-19. doi: 10.1002/chir.20560.
A model cyclohexapeptide, cyclo-(Phe-(D)Pro-Gly-Arg-Gly-Asp) was synthesized and its IR and VCD spectra were used as a test of density functional theory (DFT) level predictions of spectral intensities for a peptide with a nonrepeating but partially constricted conformation. Peptide structure and flexibility was estimated by molecular dynamics (MD) simulations and the spectra were simulated using full quantum mechanical (QM) approaches for the complete peptide and for simplified models with truncated side chains. After simulated annealing, the backbone conformation of the ring structure is relatively stable, consisting of a normal beta-turn and a tight loop (no H-bond) which does not vary over short trajectories. Only in quite long MD runs at high temperatures do other conformations appear. MD simulations were carried out for the cyclic peptide in water and in TFE, which match experimental solvents, as well as with and without protonation of the Asp carboxyl group. DFT spectral simulations were made using the annealed structure and were extended to include basis set variation, to determine an optimal computational approach, and solvent simulation with a polarized continuum model (PCM). Stepwise full DFT simulation of spectra was done for various sequences with the same backbone geometry but based on (1) solely Gly residues, (2) Ala substitution except Gly and Pro, and (3) complete sequences with side chains. Additionally, a selection of structures was used to compute IR and VCD spectra with the optimal method to determine structural variation effects. The side chains, especially the Asp-COOH and Arg-NH(2) transitions, had an impact on the computed amide frequencies, IR intensities and VCD pattern. Since experimentally these groups would have little chirality, due to conformational variation, they do not impact the observed VCD spectra. Correcting for frequency shifts, the Ala model for the cyclopeptide gives the clearest representation of the amide VCD. The experimental sign pattern for the amide I' band in D(2)O and also the sharper, more intense amide I VCD band in TFE was seen to some degree in one conformer with Type II' turns, but the data favor a mix of structures.
合成了一种典型的环己肽，环（苯丙氨酸 - （D）脯氨酸 - 甘氨酸 - 精氨酸 - 甘氨酸 - 天冬氨酸），并将其红外光谱和振动圆二色光谱用作对具有非重复但部分受限构象的肽的光谱强度进行密度泛函理论（DFT）水平预测的测试。通过分子动力学（MD）模拟估计肽的结构和柔韧性，并使用全量子力学（QM）方法对完整肽和具有截短侧链的简化模型模拟光谱。模拟退火后，环结构的主链构象相对稳定，由一个正常的β-转角和一个紧密环（无氢键）组成，在短轨迹上不会变化。只有在高温下进行相当长的MD运行时才会出现其他构象。对环肽在与实验溶剂匹配的水和三氟乙醇（TFE）中，以及天冬氨酸羧基有或无质子化的情况下进行了MD模拟。使用退火结构进行DFT光谱模拟，并扩展到包括基组变化，以确定最佳计算方法，以及使用极化连续介质模型（PCM）进行溶剂模拟。对具有相同主链几何结构的各种序列进行了光谱的逐步全DFT模拟，但基于（1）仅甘氨酸残基，（2）除甘氨酸和脯氨酸外的丙氨酸取代，以及（3）带有侧链的完整序列。此外，使用一组结构以最佳方法计算红外光谱和振动圆二色光谱，以确定结构变化的影响。侧链，特别是天冬氨酸 - 羧基和精氨酸 - 氨基的跃迁，对计算出的酰胺频率、红外强度和振动圆二色模式有影响。由于在实验中，由于构象变化，这些基团几乎没有手性，因此它们不会影响观察到的振动圆二色光谱。校正频率偏移后，环肽的丙氨酸模型给出了酰胺振动圆二色的最清晰表示。在具有II'型转角的一个构象中，在一定程度上可以看到重水（D₂O）中酰胺I'带的实验符号模式以及三氟乙醇中更尖锐、更强的酰胺I振动圆二色带，但数据支持多种结构的混合。
