Using Ligand-Induced Protein Chemical Shift Perturbations To Determine Protein-Ligand Structures.
Using Ligand-Induced Protein Chemical Shift Perturbations To Determine Protein-Ligand Structures.
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DOI：
10.1021/acs.biochem.7b00170
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发表时间：
2017-04
期刊：
影响因子：
2.9
通讯作者：
Zhuoqin Yu;Pengfei Li;K. Merz
中科院分区：
文献类型：
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作者：
Zhuoqin Yu;Pengfei Li;K. Merz
蛋白质化学位移扰动（CSP），在配体结合，可用于细化蛋白质-配体复合物的结构，通过比较实验CSP与计算CSPs的任何给定的一组结构坐标。在此，我们描述了一种快速准确的方法，该方法通过关注配体对蛋白质的影响，为使用基于核磁共振（NMR）的方法改善蛋白质-配体复合物的质量开辟了新的机会。新的计算方法，1H经验化学位移微扰（HECSP），已被开发用于快速计算配体结合诱导的蛋白质中的1H CSPs。由于缺乏实验信息，可以推导出一个模型，我们采用高质量的密度泛函理论（DFT）计算，使用自动碎片化量子力学/分子力学的方法来推导一系列蛋白质-配体复合物上的配体诱导的CSP数据库。总体而言，经验HECSP模型的预测值和DFT计算值之间的相关系数分别为0.897（1HA）、0.971（1HN）和0.945（侧链1H），均方根误差分别为0.151（1HA）、0.199（1HN）和0.257 ppm（侧链1H）。使用HECSP模型，我们开发了一个评分函数（NMRScore_P）。我们描述了NMRScore_P在两个复杂体系中的两个应用，并证明该方法可以区分天然配体和诱饵，并细化蛋白质-配体复合物的结构。我们为这两种复合物提供了进一步改进的模型，这些模型满足实验中观察到的1H CSP。总之，与NMRScore_P偶联的HECSP提供了一个准确和快速的平台，通过该平台可以使用NMR衍生的信息来精制蛋白质-配体复合物。
Protein chemical shift perturbations (CSPs), upon ligand binding, can be used to refine the structure of a protein-ligand complex by comparing experimental CSPs with calculated CSPs for any given set of structural coordinates. Herein, we describe a fast and accurate methodology that opens up new opportunities for improving the quality of protein-ligand complexes using nuclear magnetic resonance (NMR)-based approaches by focusing on the effect of the ligand on the protein. The new computational approach, 1H empirical chemical shift perturbation (HECSP), has been developed to rapidly calculate ligand binding-induced 1H CSPs in a protein. Given the dearth of experimental information by which a model could be derived, we employed high-quality density functional theory (DFT) computations using the automated fragmentation quantum mechanics/molecular mechanics approach to derive a database of ligand-induced CSPs on a series of protein-ligand complexes. Overall, the empirical HECSP model yielded correlation coefficients between its predicted and DFT-computed values of 0.897 (1HA), 0.971 (1HN), and 0.945 (side chain 1H) with root-mean-square errors of 0.151 (1HA), 0.199 (1HN), and 0.257 ppm (side chain 1H), respectively. Using the HECSP model, we developed a scoring function (NMRScore_P). We describe two applications of NMRScore_P on two complex systems and demonstrate that the method can distinguish native ligand poses from decoys and refine protein-ligand complex structures. We provide further refined models for both complexes, which satisfy the observed 1H CSPs in experiments. In conclusion, HECSP coupled with NMRScore_P provides an accurate and rapid platform by which protein-ligand complexes can be refined using NMR-derived information.