Development of QM/MM (ABEEM polarizable force field) method to simulate the excision reaction mechanism of damaged cytosine

• Published in: Journal of computational chemistry 2022-12, Vol.43 (32), p.2139-2153
• Main Authors: Liu, Cui, Ren, Yang, Gao, Xiao‐qin, Du, Xue, Yang, Zhong‐zhi
• Format: Article
• Language: English
• Subjects: Charge distribution; Charge transfer; Chemical bonds; damaged cytosine; deglycosylation mechanism; Electronegativity; Nucleophiles; polarization effect; QM/MM(ABEEM); Reaction mechanisms; Simulation
• ISSN: 0192-8651; 1096-987X
• DOI: 10.1002/jcc.27008

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. This work has developed the ABEEM fluctuating polarizable force field combining with the QM method, that is, QM/MM (ABEEM), accurately simulates the polarization effect and charge transfer. The piecewise functions are used as the valence‐state electronegativity to simulate the charge distribution of reaction accurately. The charge transfer is accurately simulated by the local charge conservation conditions. Four deglycosylation pathways including the monofunctional and difunctional mechanisms of four neutral and protonated cytosine derivatives are explored. It is confirmed that the monofunctional mechanism is a better. Protonization of the base has reduced the activation energy. Asp provides the necessary charge for the reaction.