A High-Level Quantum Chemical Study of the Thermodynamics Associated with Chlorine Transfer between N-Chlorinated Nucleobases

Geometries of the isomers of the N-Chlorinated nucleobases (adenine, guanine and thymine) as well as the lowest energy structures of the DNA bases (adenine, cytosine, guanine and thymine) obtained at the B3LYP/6-31G(2df,p) level of theory (in Cartesian Coordinates). <strong>ABSTRACT: </strong>The relative free energies of the isomers formed upon <em>N</em>-chlorination of each nitrogen atom within the DNA nucleobases (adenine, guanine, and thymine) have been obtained using the high-level G4(MP2) composite ab initio method (the free energies of the <em>N</em>-chlorinated isomers of cytosine have been reported at the same level of theory previously). Having identified the lowest energy <em>N</em>-chlorinated derivatives for each nucleobase, we have computed the free energies associated with chlorine transfer from <em>N</em>-chlorinated nucleobases to other unsubstituted bases. Our results provide quantitative support pertaining to the results of previous experimental studies, which demonstrated that rapid chlorine transfer occurs from an <em>N</em>-chlorothymidine to cytidine or adenosine. The results of our calculations in the gas-phase reveal that chlorine transfer from <em>N</em>-chlorothymine to either cytosine, adenine, or guanine proceed via exergonic processes with D<em>G</em>^o values of ­–50.3 (cytosine), –28.0 (guanine), and –6.7 (adenine) kJ mol^–1. Additionally, we consider the effect of aqueous solvation by augmenting our gas-phase G4(MP2) energies with solvation corrections obtained using the conductor-like polarizable continuum model. In an aqueous solution, we obtain the following G4(MP2) free energies associated with chlorine transfer from <em>N</em>-chlorothymine to the three other nucleobases: –58.4 (cytosine), –26.4 (adenine), and –18.7 (guanine) kJ mol^–1. Therefore, our calculations, whether in the gas phase or in an aqueous solution, clearly indicate that chlorine transfer from any of the <em>N</em>-chlorinated nucleobases to cytosine provides a thermodynamic sink for the active chlorine. This thermodynamic preference for chlorine transfer to cytidine may be particularly deleterious since previous experimental studies have shown that nitrogen-centered radical formation (via N–Cl bond homolysis) is more easily achieved in <em>N</em>-chlorinated cytidine than in other <em>N</em>-chlorinated nucleosides.本数据集包含经B3LYP/6-31G(2df,p)理论级别计算得到的N-氯化核碱基（N-Chlorinated nucleobases）的异构体几何构型，以及DNA碱基（腺嘌呤（adenine）、胞嘧啶（cytosine）、鸟嘌呤（guanine）、胸腺嘧啶（thymine））的最低能量结构，数据格式为笛卡尔坐标（Cartesian Coordinates）。【摘要：】本研究采用G4(MP2)复合从头算方法（G4(MP2) composite ab initio method），计算了DNA核碱基（腺嘌呤、鸟嘌呤、胸腺嘧啶）中各氮原子经N-氯化后生成的异构体的相对自由能（此前已有报道采用相同理论级别计算得到了胞嘧啶的N-氯化异构体自由能）。在确定每种核碱基的最低能量N-氯化衍生物后，我们计算了氯从N-氯化核碱基转移至其他未取代碱基（unsubstituted bases）的相关自由能。本研究结果为既往实验研究结论提供了定量支撑：此前实验已证实，氯可从N-氯化胸苷快速转移至胞苷或腺苷。气相计算结果显示，氯从N-氯化胸腺嘧啶转移至胞嘧啶、腺嘌呤或鸟嘌呤的过程均为放能过程（exergonic processes），其标准吉布斯自由能变（ΔG°）分别为–50.3（胞嘧啶）、–28.0（鸟嘌呤）和–6.7（腺嘌呤）kJ·mol⁻¹。此外，我们采用导体类可极化连续介质模型（conductor-like polarizable continuum model）计算溶剂化校正能，对气相G4(MP2)能量进行修正，以此考察水溶液溶剂化效应的影响。在水溶液环境中，氯从N-氯化胸腺嘧啶转移至其余三种核碱基的G4(MP2)自由能分别为：–58.4（胞嘧啶）、–26.4（腺嘌呤）和–18.7（鸟嘌呤）kJ·mol⁻¹。因此，无论气相还是水溶液环境下的计算结果均明确显示：氯从任意N-氯化核碱基转移至胞嘧啶的过程，会使活性氯形成热力学阱（thermodynamic sink）。这种氯优先转移至胞苷的热力学偏好可能具有特殊危害性，因为既往实验研究表明，相较于其他N-氯化核苷，N-氯化胞苷更易通过N–Cl键均裂（homolysis）生成氮中心自由基。