摘要
6-甲基腺嘌呤(N~6-methyladenosine,m6A)是真核生物mRNA内部序列中最常见的一种转录后的修饰形式。最近几年,很多研究者报道了这种甲基化修饰对生命活动的调控和影响,在生物水平上阐释了这种甲基化修饰的生物学意义。但是,在分子水平上,机理的研究还尚不成熟。从这个角度来看,6-甲基腺嘌呤(N~6-methyladenosine,m6A)是发生在胞嘧啶碱基第六位N原子上的甲基化。我们首先通过晶体结构(PDB:2mvs)~([1])确定m6A结构,然后利用密度泛函的方法,计算得到6-甲基腺嘌呤的电荷分布,然后在Amber12现有力场模板的基础上,合理构建了6-甲基腺嘌呤的结构和力场参数。通过一系列的量化计算与分子模拟,我们解释了6-甲基腺嘌呤阻碍DNA或RNA合成过程的原因——即腺嘌呤第六位N原子上的甲基的位阻影响了核酸糖环C2'-endo与C3'-endo构象的转变,妨碍了其与模板链在合成酶空腔内的互补配对(Fig.1)~([2])。
N~6-methyladenosine(m6A) is a post-transcriptional modification of RNAs.In recent year,many scientists have reported the effect of biofunctionability caused by such modification.However,the investigation about the mechanisms on a molecular level used to be insufficient.So,we built the molecular model from convinced crystal structure(PDB:2mvs),then got the charge distribution by the DFT method.After that,a novel force fields were built base on the canonical adenine force fields in Amber 12 and our quantum chemical calculation.With the help of such force fields,the efficient molecular simulation was carried out to investigate the hindering effect caused by N-methyladenosine in the process of RNA- or DNA- directed DNA synthesis.
引文
[1]Roost,C.;Lynch,S.R.;Batista,P.J.;Qu,K.;Chang,H.Y.;Kool,E.T.J.Am.Chem.Soc.2015,137:2107.
[2]Wang S.;Wang J.;Zhang X.;Fu B.;Zhou X.;Zhang X.;Tian T.;Zhou X.Chem.Sci.2015,6:3013.
