An improved, time-efficient approach to extract accurate distance restraints for NMR2 structure calculation

Q3 Physics and Astronomy
Aditya Pokharna, Felix Torres, Harindranath Kadavath, J. Orts, R. Riek
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引用次数: 0

Abstract

Abstract. Exact nuclear Overhauser enhancement (eNOE) yields highly accurate, ensemble averaged 1H–1H distance restraints with an accuracy of up to 0.1 Å for the multi-state structure determination of proteins as well as for nuclear magnetic resonance molecular replacement (NMR2) to determine the structure of the protein–ligand interaction site in a time-efficient manner. However, in the latter application, the acquired eNOEs lack the obtainable precision of 0.1 Å because of the asymmetrical nature of the filtered nuclear Overhauser enhancement spectroscopy (NOESY) experiment used in NMR2. This error is further propagated to the eNOE equations used to fit and extract the distance restraints. In this work, a new analysis method is proposed to obtain inter-molecular distance restraints from the filtered NOESY spectrum more accurately and intuitively by dividing the NOE cross peak by the corresponding diagonal peak of the ligand. The method termed diagonal-normalised eNOEs was tested on the data acquired by Torres et al. (2020) on the complex of PIN1 and a small, weak-binding phenylimidazole fragment. NMR2 calculations performed using the distances derived from diagonal-normalised eNOEs yielded the right orientation of the fragment in the binding pocket and produced a structure that more closely resembles the benchmark X-ray structure (2XP6) (Potter et al., 2010) with an average heavy-atom root-mean-square deviation (RMSD) of 1.681 Å with respect to it, when compared to the one produced with traditional NMR2 with an average heavy atom RMSD of 3.628 Å. This is attributed to the higher precision of the evaluated distance restraints.
一种改进的、省时的NMR2结构精确距离约束提取方法
摘要精确核Overhauser增强(eNOE)产生了高精度的系综平均1H–1H距离约束,精度高达0.1 Å用于蛋白质的多态结构测定以及核磁共振分子置换(NMR2),以高效的方式测定蛋白质-配体相互作用位点的结构。然而,在后一种应用中,所获取的eNOE缺乏0.1的可获得精度 Å,因为NMR2中使用的过滤核Overhauser增强光谱(NOESY)实验的不对称性质。该误差被进一步传播到用于拟合和提取距离约束的eNOE方程。在这项工作中,提出了一种新的分析方法,通过将NOE交叉峰除以配体的相应对角峰,从过滤后的NOESY光谱中更准确、直观地获得分子间距离约束。在Torres等人获得的数据上测试了称为对角归一化eNOEs的方法。(2020)关于PIN1和小的、弱结合的苯基咪唑片段的复合物。使用从对角线归一化eNOEs导出的距离进行的NMR2计算产生了结合口袋中片段的正确方向,并产生了更接近基准X射线结构(2XP6)的结构(Potter等人,2010),平均重原子均方根偏差(RMSD)为1.681 Å,与传统NMR2产生的平均重原子RMSD为3.628的NMR2相比 Å。这是由于评估的距离约束具有更高的精度。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
4.50
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审稿时长
14 weeks
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