Centro de Investigación de Estudios Avanzados del Maule (CIEAM), Vicerrectorá de Investigación y Postgrado Universidad Católica del Maule, Talca 3480112, Chile.
Laboratorio de Bioinformática y Química Computacional (LBQC), Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca 3480112, Chile.
Phys Chem Chem Phys. 2024 Mar 6;26(10):8210-8218. doi: 10.1039/d3cp05742a.
Proper description of solvent effects is challenging for theoretical methods, particularly if the solute is a zwitterion. Here, a series of theoretical procedures are used to determine the preferred solvated conformations of twelve hydrophobic dipeptides (Leu-Leu, Leu-Phe, Phe-Leu, Ile-Leu, Phe-Phe, Ala-Val, Val-Ala, Ala-Ile, Ile-Ala, Ile-Val, Val-Ile and Val-Val) in the zwitterionic state. First, the accuracy of density functional theory (DFT), combined with different implicit solvent models, for describing zwitterions in aqueous solvent is assessed by comparing the predicted against the experimental glycine tautomerization energy, , the energetic difference between canonical and zwitterionic glycine in aqueous solvents. It is found that among the tested solvation schemes, the charge-asymmetric nonlocally determined local-electric solvation model (CANDLE) predicts an energetic difference in excellent agreement with the experimental value. Next, DFT-CANDLE is used to determine the most favorable solvated conformation for each of the investigated dipeptide zwitterions. The CANDLE-solvated structures are obtained by exploring the conformational space of each dipeptide zwitterion concatenating DFT calculations, in vacuum, with classical molecular dynamics simulations, in explicit solvents, and DFT calculations including explicit water molecules. It is found that the energetically most favorable conformations are similar to those of the dipeptide zwitterions in their respective crystal structures. Such structural agreement is indicative of the DFT-CANDLE accomplishment of the description of solvated zwitterions, and suggests that these biomolecules self-assemble as quasi-rigid objects.
准确描述溶剂效应对理论方法来说是一个挑战，特别是对于两性离子溶质。在这里，我们使用了一系列理论程序来确定 12 种疏水性二肽（亮氨酸-亮氨酸、亮氨酸-苯丙氨酸、苯丙氨酸-亮氨酸、异亮氨酸-亮氨酸、苯丙氨酸-苯丙氨酸、丙氨酸-缬氨酸、缬氨酸-丙氨酸、丙氨酸-异亮氨酸、异亮氨酸-丙氨酸、异亮氨酸-缬氨酸、缬氨酸-异亮氨酸和缬氨酸-缬氨酸）在两性离子状态下的优先溶剂化构象。首先，通过比较预测的甘氨酸互变异构化能与实验值，评估密度泛函理论（DFT）结合不同的隐式溶剂模型对水溶剂中两性离子的描述准确性，其中， 表示经典甘氨酸和两性离子甘氨酸在水溶剂中的能量差。结果表明，在所测试的溶剂化方案中，电荷非对称非局部确定的局部电场溶剂化模型（CANDLE）预测的能量差与实验值非常吻合。接下来，我们使用 DFT-CANDLE 来确定所研究的二肽两性离子中每种最有利的溶剂化构象。通过在真空中串联 DFT 计算与经典分子动力学模拟在显式溶剂中，以及包括显式水分子的 DFT 计算，探索每个二肽两性离子的构象空间，获得 CANDLE 溶剂化结构。结果表明，能量上最有利的构象与各自晶体结构中二肽两性离子的构象相似。这种结构上的一致性表明，DFT-CANDLE 能够准确描述溶剂化的两性离子，并且表明这些生物分子作为准刚性物体自组装。
