Faculty of Exact and Applied Sciences, Instituto Tecnológico Metropolitano, Medellín 050034, Colombia.
Faculty of Basic Sciences, University of Medellin, Medellín 050026, Colombia.
Int J Mol Sci. 2023 Feb 2;24(3):2923. doi: 10.3390/ijms24032923.
Betanidin (Bd) is a nitrogenous metabolite with significant bioactive potential influenced by pH. Its free radical scavenging activity and deprotonation pathway are crucial to studying its physicochemical properties. Motivated by the published discrepancies about the best deprotonation routes in Bd, this work explores all possible pathways for proton extractions on that molecule, by using the direct approach method based on pK. The complete space of exploration is supported by a linear relation with constant slope, where the pK is written in terms of the associated deprotonated molecule energy. The deprotonation rounds 1, …, 6 define groups of parallel linear models with constant slope. The intercepts of the models just depend on the protonated energy for each round, and then the pK can be trivially ordered and explained by the energy. We use the direct approximation method to obtain the value of pK. We predict all possible outcomes based on a linear model of the energy and some related verified assumptions. We also include a new measure of similarity or dissimilarity between the protonated and deprotonated molecules, via a geometric-chemical descriptor called the Riemann-Mulliken distance (RMD). The RMD considers the cartesian coordinates of the atoms, the atomic mass, and the Mulliken charges. After exploring the complete set of permutations, we show that the successive deprotonation process does not inherit the local energy minimum and that the commutativity of the paths does not hold either. The resulting clusterization of pK can be explained by the local acid and basic groups of the BD, and the successive deprotonation can be predicted by using the chemical explained linear models, which can avoid unnecessary optimizations. Another part of the research uses our own algorithm based on shape theory to determine the protein's active site automatically, and molecular dynamics confirmed the results of the molecular docking of Bd in protonated and anionic form with the enzyme aldose reductase (AR). Also, we calculate the descriptors associated with the SET and SPLET mechanisms.
甜菜因（Bd）是一种含氮代谢物，具有重要的生物活性潜力，受 pH 值影响。其自由基清除活性和去质子化途径对于研究其物理化学性质至关重要。由于发表的关于 Bd 最佳去质子化途径的差异，本工作通过基于 pK 的直接方法探索了该分子上所有可能的质子提取途径。探索的完整空间由具有恒定斜率的线性关系支持，其中 pK 用相关的去质子化分子能量表示。去质子化轮 1、...、6 定义了具有恒定斜率的平行线性模型组。模型的截距仅取决于每轮质子化的能量，然后可以通过能量轻松对 pK 进行排序和解释。我们使用直接逼近方法获得 pK 的值。我们根据能量的线性模型和一些相关的验证假设预测所有可能的结果。我们还通过称为里曼-穆利肯距离（RMD）的几何化学描述符来测量质子化和去质子化分子之间的相似性或差异性。RMD 考虑了原子的笛卡尔坐标、原子质量和 Mulliken 电荷。在探索完所有可能的排列组合后，我们发现连续的去质子化过程不会继承局部能量最小值，而且路径的交换律也不成立。所得 pK 的聚类可以用 Bd 的局部酸和碱性基团来解释，并且可以通过使用化学解释线性模型来预测连续的去质子化，这可以避免不必要的优化。研究的另一部分使用我们自己基于形状理论的算法自动确定蛋白质的活性位点，并通过分子动力学确认了质子化和阴离子形式的 Bd 与醛糖还原酶（AR）的分子对接结果。此外，我们计算了与 SET 和 SPLET 机制相关的描述符。
