Predicting the Mechanism of Demethylation of Nucleobases in Theoretical Simulation: A Review

DNA or RNA methylation is a significant dynamic regulation process in regulating human gene expression which could be generated by endogenous substances, exogenous reagents, or radiation. The damaged DNA or RNA may lead to mutations that compromise epigenetic patterns, block DNA and RNA synthesis, and affect the coding of mRNA transcription and translation. Interestingly, it is a reversal process that could be modified by demethylases. Scientists have discovered that ten-eleven translocation proteins (TET) and AlkB family enzymes could repair these damaged DNA or RNA, meanwhile, they are both α-ketoglutarate (α-KG)/Fe(II)-dependent proteins. The detailed mechanism of the reaction is still unknown although intermediates in some nucleobases demethylation reactions have been measured experimentally. Recently, quantum mechanics/ molecular mechanics (QM/MM) methods are becoming a hot research topic to predict mechanisms of catalytic reactions. This review summarizes and comments on many cases in which computational methods have been used to predict the detailed mechanisms of the demethylation of nucleobases.