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Development of QM/MM (ABEEM polarizable force field) method to simulate the excision reaction mechanism of damaged cytosine
Journal of Computational Chemistry ( IF 3.4 ) Pub Date : 2022-09-24 , DOI: 10.1002/jcc.27008 Cui Liu 1 , Yang Ren 1 , Xiao-Qin Gao 1 , Xue Du 1 , Zhong-Zhi Yang 1
Journal of Computational Chemistry ( IF 3.4 ) Pub Date : 2022-09-24 , DOI: 10.1002/jcc.27008 Cui Liu 1 , Yang Ren 1 , Xiao-Qin Gao 1 , Xue Du 1 , Zhong-Zhi Yang 1
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DNA damages are regarded as having harmful effects on cell. The base excision repair mechanism combats these effects by removing damaged bases. The deglycosylation mechanism of excising damaged bases by DNA glycosylase and the state of the leaving base have been controversial. The enzymatic reaction of DNA glycosylase to remove the damaged bases involves not only the formation and breaking of chemical bonds, but also complex polarization effect and charge transfer, which cannot be accurately simulated by the QM/MM method combined with the fixed charge force field. This work has developed the ABEEM fluctuating polarizable force field combining with the QM method, that is (QM/MM[ABEEM]), to accurately simulate the proton transfer, charge transfer and the charge distribution. The piecewise function is used as the valence-state electronegativity in the QM/MM (ABEEM) to realize the accurate fitting of the charge distribution in reaction. And the charge transfer is accurately simulated by the local charge conservation conditions. Four deglycosylation mechanisms including the monofunctional and difunctional mechanisms of four neutral and protonated cytosine derivatives are explored. It is confirmed that the monofunctional mechanism of Asp-activated nucleophile water is a better deglycosylation mechanism and the base is protonated before the reaction occurs. Protonization of the base reduced the activation energy by 10.00–17.00 kcal/mol. Asp provides the necessary charge for the reaction, and DNA glycosylase preferentially cleaves ɛC. This work provides a theoretical basis for the research of excising damaged bases by DNA glycosylase.
中文翻译：
开发 QM/MM（ABEEM 极化力场）方法模拟受损胞嘧啶的切除反应机制
DNA损伤被认为对细胞有有害影响。碱基切除修复机制通过去除受损碱基来对抗这些影响。DNA糖基化酶切除受损碱基的去糖基化机制和离去碱基的状态一直存在争议。DNA糖基化酶去除受损碱基的酶促反应不仅涉及化学键的形成和断裂，还涉及复杂的极化效应和电荷转移，QM/MM方法结合固定电荷力场无法准确模拟。本工作开发了与QM方法相结合的ABEEM波动极化力场，即(QM/MM[ABEEM])，以准确模拟质子转移、电荷转移和电荷分布。QM/MM（ABEEM）中使用分段函数作为价态电负性，实现对反应中电荷分布的精确拟合。并且通过局部电荷守恒条件准确地模拟了电荷转移。探索了四种去糖基化机制，包括四种中性和质子化胞嘧啶衍生物的单功能和双功能机制。证实Asp-activated nucleophile water的单功能机制是更好的去糖基化机制，碱基在反应发生前被质子化。碱基的质子化使活化能降低了 10.00–17.00 kcal/mol。Asp 为反应提供必要的电荷，DNA 糖基化酶优先切割 εC。
更新日期：2022-09-24
中文翻译：
开发 QM/MM（ABEEM 极化力场）方法模拟受损胞嘧啶的切除反应机制
DNA损伤被认为对细胞有有害影响。碱基切除修复机制通过去除受损碱基来对抗这些影响。DNA糖基化酶切除受损碱基的去糖基化机制和离去碱基的状态一直存在争议。DNA糖基化酶去除受损碱基的酶促反应不仅涉及化学键的形成和断裂，还涉及复杂的极化效应和电荷转移，QM/MM方法结合固定电荷力场无法准确模拟。本工作开发了与QM方法相结合的ABEEM波动极化力场，即(QM/MM[ABEEM])，以准确模拟质子转移、电荷转移和电荷分布。QM/MM（ABEEM）中使用分段函数作为价态电负性，实现对反应中电荷分布的精确拟合。并且通过局部电荷守恒条件准确地模拟了电荷转移。探索了四种去糖基化机制，包括四种中性和质子化胞嘧啶衍生物的单功能和双功能机制。证实Asp-activated nucleophile water的单功能机制是更好的去糖基化机制，碱基在反应发生前被质子化。碱基的质子化使活化能降低了 10.00–17.00 kcal/mol。Asp 为反应提供必要的电荷，DNA 糖基化酶优先切割 εC。
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