Tolosa S, Sansón J A, Hidalgo A
Departamento de Ingeniería Química y Química Física, Universidad de Extremadura Badajoz Spain
RSC Adv. 2018 Oct 11;8(61):34867-34876. doi: 10.1039/c8ra07390b. eCollection 2018 Oct 10.
Gibbs free energy profiles of the cytosine deamination assisted by a water molecule in a discrete aqueous medium were obtained by the application of Steered Molecular Dynamic (SMD) simulations. Two pathways were considered to explain the mechanism of this process, where the water molecule attacks the C-N bond to give an intermediate (an amino-hydroxy-oxo structure in the A-path, and a hydroxy-oxo in the B-path) as the determinant step of reaction. Stationary structures along both energy profiles were analyzed at molecular dynamics level, obtaining states with higher free energies than those from electronic calculations in the gas phase and in solution described as a continuous medium. From the results obtained, the more complex A-pathway, with five steps, was kinetically the most favorable (with an endergonic reaction energy of 7.41 kcal mol, a high barrier of 67.53 kcal mol, and a small velocity constant = 1.80 × 10 s), concluding that the uracil base can participate in a spontaneous genetic mutation since the uracil-ammonia complex has a long lifetime of 6.10 × 10 s. This process turns out exergonic and faster when carried out in gas phase simulation or electronic calculation with a continuous medium, due to the disappearance of explicit water molecules that can compete with the assistant molecule.
通过应用引导分子动力学（SMD）模拟，获得了离散水介质中水分子辅助胞嘧啶脱氨的吉布斯自由能分布。考虑了两条途径来解释该过程的机制，其中水分子攻击C-N键以产生中间体（A途径中的氨基-羟基-氧代结构和B途径中的羟基-氧代结构）作为反应的决定性步骤。在分子动力学水平上分析了沿两个能量分布的稳定结构，获得的状态比气相和作为连续介质描述的溶液中的电子计算结果具有更高的自由能。从获得的结果来看，更复杂的有五步的A途径在动力学上最有利（反应能量为7.41千卡/摩尔的吸热反应，高势垒为67.53千卡/摩尔，小速度常数 = 1.80×10秒），得出结论，尿嘧啶碱基可以参与自发基因突变，因为尿嘧啶-氨络合物具有6.10×10秒的长寿命。当在气相模拟或使用连续介质的电子计算中进行时，由于与辅助分子竞争的明确水分子消失，该过程结果是放热且更快的。
