Molecular dynamics study
Molecular dynamics study
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发表时间：
1997
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通讯作者：
T. Sayle;J. Goodfellow
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作者：
T. Sayle;J. Goodfellow
我们目前的数据来解释在O 6位置的鸟嘌呤的烷基化的序列依赖性。O 6-鸟嘌呤的甲基化和乙基化都发生在DNA双螺旋d（5@GGCGCTGGAGGCGTG-3@）中中间密码子GGA的第一位或第二位。从我们的分子动力学研究，参数，如氢键，表面可及性和均方根偏差，提供了一个原子的基本原理的事实，即该序列的中间密码子的第二个鸟嘌呤是在这个序列中的烷基化的优选位点。此外，O 6-烷基鸟嘌呤-DNA烷基转移酶（AGT）的识别和修复对第二位烷基化的效率低于第一位，并且对O 6乙基鸟嘌呤（O 6-etG）的效率也低于对O 6-甲基鸟嘌呤（O 6-meG）的效率。DNA双链体中碱基之间的错配可能由于化学修饰而发生，并可能导致突变和可能的致癌病变。因此，重要的是，我们研究和理解这些修改的性质。一种这样的修饰基是O 6-烷基鸟嘌呤（O 6 alkylG）艾德。在DNA双链体中，它可以与胞嘧啶（C）氢键结合，但具有摆动构象而不是正常的沃森-克里克构象，由于胞嘧啶滑入小沟而导致骨架的局部破坏。O 6-烷基鸟嘌呤也可以与胸腺嘧啶（T）配对，这是一种通过这些碱基之间的两个氢键稳定的错配，结果是碱基对具有与正常WatsonE Crick碱基配对相似的总体构象。该O 6-烷基鸟嘌呤：胸腺嘧啶（O 6烷基G：T）容易错配成正常的双链DNA，并且可能难以被修复酶识别，从而导致G到A突变。
We present data to explain the sequence dependence of alkylation at the O6 position of guanine. Both methylation and ethylation of O6-guanine occur at either the ‐rst or the second position of the middle codon, GGA, in the DNA double helix d(5@GGCGCTGGAGGCGTG-3@). From our molecular dynamics studies, parameters such as hydrogen bonding, surface accessibility and root-mean-square deviation, provide an atomic rationale for the fact that the second guanine of the middle codon of the sequence is the preferred site for alkylation in this sequence. Furthermore, the recognition and repair by O6-alkylguanine-DNA alkyl transferase (AGT) is less e†ective for alkylation at the second position than the ‐rst, and is also less e†ective for O6ethylguanine (O6-etG) than for O6-methylguanine (O6-meG). Mismatches between bases in DNA duplexes can occur because of chemical modi‐cation and can lead to mutations and possible carcinogenic lesions. It is, therefore, important that we study and understand the nature of these modi‐cations. One such modi‐ed base is O6-alkylguanine (O6alkylG). In DNA duplexes, it can hydrogen bond to cytosine (C) but with a wobble conformation rather than the normal WatsonECrick conformation, resulting in local disruption of the backbone due to the sliding of cytosine into the minor groove. O6-alkylguanine can also pair with thymine (T), a mismatch which is stabilized by two hydrogen bonds between these bases, with the consequence that the base pair has a similar overall conformation to that of the normal WatsonE Crick base pairing. This O6-alkylguanine : thymine (O6alkylG : T) mispair ‐ts easily into normal duplex DNA and may be difficult to recognise by repair enzymes thus leading to G to A mutations.