Time Averaging of NMR Chemical Shifts in the MLF Peptide in the Solid State
Time Averaging of NMR Chemical Shifts in the MLF Peptide in the Solid State
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DOI：
10.1021/ja9062629
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发表时间：
2010-05-05
影响因子：
15
通讯作者：
Vendruscolo, Michele
中科院分区：
文献类型：
--
作者：
De Gortari, Itzam;Portella, Guillem;Vendruscolo, Michele
由于核磁共振化学位移的实验测量提供了时间和集合平均值，我们研究了使用密度泛函理论（DFT）计算化学位移时应如何包括这些影响。我们测量了n -甲酰基-l -甲硫基-l -亮基-l -苯丙氨酸- ome （MLF）肽在固体状态下的化学位移，然后利用x射线结构计算了C-13的化学位移，其中包括投影增强波（GIPAW）方法，该方法考虑了晶体结构的周期性，获得了4.2 ppm的总体精度。为了了解实验和计算化学位移之间差异的来源，我们进行了第一性原理分子动力学模拟，以表征皮秒时间尺度上MLF肽的分子运动。我们发现，碳-13的化学变化经历了超过20ppm的快速波动，平均波动时间不到200fs。在计算化学位移时考虑到这些波动，准确度为3.3 ppm。为了研究在更长的时间尺度上平均的影响，我们通过进行总共5 μ s的经典分子动力学模拟，对固态中MLF肽填充的旋转态进行了采样。通过平均这些旋转状态的化学位移，我们将化学位移计算的精度提高到3.0 ppm，在22种情况中有10种误差小于1 ppm。这些结果表明，通过开发改进的计算策略，能够考虑到化学位移测量报告的毫秒时间尺度的平均过程，可以实现更好的基于dft的肽和蛋白质化学位移预测。
Since experimental measurements of NMR chemical shifts provide time and ensemble averaged values, we investigated how these effects should be included when chemical shifts are computed using density functional theory (DFT). We measured the chemical shifts of the N-formyl-L-methionyl-L-leucyl-L-phenylalanine-OMe (MLF) peptide in the solid state, and then used the X-ray structure to calculate the C-13 chemical shifts using the gauge including projector augmented wave (GIPAW) method, which accounts for the periodic nature of the crystal structure, obtaining an overall accuracy of 4.2 ppm. In order to understand the origin of the difference between experimental and calculated chemical shifts, we carried out first-principles molecular dynamics simulations to characterize the molecular motion of the MLF peptide on the picosecond time scale. We found that C-13 chemical shifts experience very rapid fluctuations of more than 20 ppm that are averaged out over less than 200 fs. Taking account of these fluctuations in the calculation of the chemical shifts resulted in an accuracy of 3.3 ppm. To investigate the effects of averaging over longer time scales we sampled the rotameric states populated by the MLF peptides in the solid state by performing a total of 5 mu s classical molecular dynamics simulations. By averaging the chemical shifts over these rotameric states, we increased the accuracy of the chemical shift calculations to 3.0 ppm, with less than 1 ppm error in 10 out of 22 cases. These results suggests that better DFT-based predictions of chemical shifts of peptides and proteins will be achieved by developing improved computational strategies capable of taking into account the averaging process up to the millisecond time scale on which the chemical shift measurements report.