Human GMP reductase (hGMPR) enzyme is involved in a cellular metabolic pathway, converting GMP into IMP, and also it is an important target for anti-leukemic agents. Present computational investigations explain dynamical behavior of water molecules during the conformational transition process from GMP to IMP using molecular dynamics simulations. Residues at substrate-binding site of cancerous protein (PDB Id. 2C6Q) are mostly more dynamic in nature than the normal protein (PDB Id. 2BLE). Nineteen conserved water molecules are identified at the GMP/IMP binding site and are classified as (i) conserved stable dynamic and (ii) infrequent dynamic. Water molecules W11, W14, and W16 are classified as conserved stable dynamic due to their immobile character, whereas remaining water molecules (W1, W2, W3, W4, W5, W7, W8, W9, W10, W12, W13, W15, W17, W18, and W19) are infrequent with dynamic nature. Entrance or displacement of these infrequent water molecules at GMP/IMP sites may occur due to forward and backward movement of reference residues involving ligands. Four water molecules of hGMPR-I and nine water molecules of hGMPR-II are observed in repetitive transitions from GMP to IMP pathway, which indicates discrimination between two isoforms of hGMPRs. Water molecules in cancerous protein are more dynamic and unstable compared to normal protein. These water molecules execute rare dynamical events at GMP binding site and could assist in detailed understanding of conformational transitions that influence the hGMPR's biological functionality. The present study should be of interest to the experimental community engaged in leukemia research and drug discovery for CML cancer.

中文翻译：

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对人 GMPR 酶的 GMP 或 IMP 结合位点处水分子动力学的新生化见解：分子动力学研究

人 GMP 还原酶 (hGMPR) 酶参与细胞代谢途径，将 GMP 转化为 IMP，也是抗白血病药物的重要靶标。目前的计算研究使用分子动力学模拟解释了水分子在从 GMP 到 IMP 的构象转变过程中的动力学行为。癌性蛋白（PDB Id. 2C6Q）底物结合位点的残基在本质上比正常蛋白（PDB Id. 2BLE）更具动态性。在 GMP/IMP 结合位点鉴定出 19 个保守的水分子，并分类为 (i) 保守的稳定动态和 (ii) 不常见的动态。水分子 W11、W14 和 W16 由于其固定特性而被归类为守恒稳定动态，而剩余的水分子（W1、W2、W3、W4、W5、W7、W8、W9、W10、W12、W13、W15、W17 , W18, 和 W19) 很少见，具有动态特性。由于涉及配体的参考残基的向前和向后移动，可能会在 GMP/IMP 位点进入或置换这些不常见的水分子。在从 GMP 到 IMP 途径的重复转变中观察到 hGMPR-I 的四个水分子和 hGMPR-II 的九个水分子，这表明 hGMPR 的两种同种型之间存在差异。与正常蛋白质相比，癌变蛋白质中的水分子更具活力和不稳定。这些水分子在 GMP 结合位点执行罕见的动力学事件，可以帮助详细了解影响 hGMPR 生物学功能的构象转变。从事白血病研究和 CML 癌症药物发现的实验团体应该对本研究感兴趣。