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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Electrostatic complementarity in an aldose reductase complex from ultra-high-resolution crystallography and first-principles calculations.
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Electrostatic complementarity in an aldose reductase complex from ultra-high-resolution crystallography and first-principles calculations.

机译：醛糖还原酶复合物中的静电互补性来自超高分辨率晶体学和第一性原理计算。

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摘要

The electron density and electrostatic potential in an aldose reductase holoenzyme complex have been studied by density functional theory (DFT) and diffraction methods. Aldose reductase is involved in the reduction of glucose in the polyol pathway by using NADPH as a cofactor. The ultra-high resolution of the diffraction data and the low thermal-displacement parameters of the structure allow accurate atomic positions and an experimental charge density analysis. Based on the x-ray structural data, order-N DFT calculations have been performed on subsets of up to 711 atoms in the active site of the molecule. The charge density refinement of the protein was performed with the program mopro by using the transferability principle and our database of charge density parameters built from crystallographic analyses of peptides and amino acids. Electrostatic potentials calculated from the charge density database, the preliminary experimental electron density analysis, DFT computations, and atomic charges taken from the amber software dictionary are compared. The electrostatic complementarity between the cofactor NADP+ and the active site shows up clearly. The anchoring of the inhibitor is due mainly to hydrophobic forces and to only two polar interaction sites within the enzyme cavity. The potentials calculated by x-ray and DFT techniques agree reasonably well. At the present stage of the refinement, the potentials obtained directly from the database are in excellent agreement with the experimental ones. In addition, these results demonstrate the significant contribution of electron lone pairs and of atomic polarization effects to the host and guest mechanism.
机译：通过密度泛函理论（DFT）和衍射法研究了醛糖还原酶全酶复合物中的电子密度和静电势。通过使用NADPH作为辅因子，醛糖还原酶参与多元醇途径中葡萄糖的减少。衍射数据的超高分辨率和结构的低热位移参数可实现精确的原子位置和实验电荷密度分析。基于X射线结构数据，已对分子活性位点中多达711个原子的子集执行了N次DFT计算。蛋白质的电荷密度细化是使用mopro程序通过转移性原理和我们的电荷密度参数数据库完成的，该数据库是根据肽和氨基酸的晶体学分析建立的。比较了从电荷密度数据库计算出的静电势，初步的实验电子密度分析，DFT计算和从琥珀色软件字典中获得的原子电荷。辅助因子NADP +和活性位点之间的静电互补性很明显。抑制剂的锚固主要是由于疏水力和酶腔内只有两个极性相互作用位点。通过X射线和DFT技术计算出的电势相当吻合。在改进的当前阶段，直接从数据库获得的电势与实验电势极佳。此外，这些结果证明了电子孤对和原子极化效应对主体和客体机理的重大贡献。

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