Fernandes Pedro Alexandrino, Ramos Maria João
REQUIMTE/Faculdade de Ciências do Porto, Rua do Campo Alegre, 687, 4169-007, Portugal.
Chemistry. 2004 Jan 5;10(1):257-66. doi: 10.1002/chem.200305343.
The mechanism for thiol/disulfide exchange has been studied with high-level theoretical calculations. Free energies, transition structures, charge densities, and solvent effects along the reaction pathway have been determined for the first time. Mechanistic results agree with experimental data, and support the idea that the thiolate is the reacting species and that the reaction indeed proceeds through an uncomplicated S(N)2 transition state. The transition structures have the charge density evenly concentrated in the attacking and leaving sulfur atoms. The charge densities allow us to rationalize the solvent effects. As transition structures have the charge density more widely distributed than reactants, hydrophobic environments catalyze the reaction. The effect can be so dramatic that disulfide exchange inside the active site of ribonucleotide reductase is estimated to be catalyzed 10(3) times faster than the reaction in water. It was also found that attack by thiol is much faster than previously assumed, if mediated through water chains. Although the present results, as well as experimental data, still suggest that thiolate is the main reaction species, water-mediated thiol attack is almost kinetically competitive, and can eventually become competitive under specific experimental conditions.
已通过高水平理论计算研究了硫醇/二硫键交换的机制。首次确定了反应途径上的自由能、过渡结构、电荷密度和溶剂效应。机理结果与实验数据一致，并支持硫醇盐是反应物种的观点，且反应确实是通过简单的S(N)2过渡态进行的。过渡结构的电荷密度均匀地集中在进攻和离去的硫原子上。电荷密度使我们能够合理地解释溶剂效应。由于过渡结构的电荷密度比反应物分布得更广泛，疏水环境会催化反应。这种效应可能非常显著，以至于据估计核糖核苷酸还原酶活性位点内的二硫键交换比在水中的反应快10³倍。还发现，如果通过水链介导，硫醇的进攻比以前假设的要快得多。尽管目前的结果以及实验数据仍然表明硫醇盐是主要的反应物种，但水介导的硫醇进攻在动力学上几乎具有竞争力，并且在特定实验条件下最终可能变得具有竞争力。
