A hypothesis for what conformation of the major adduct of (+)-anti-B[a]PDE (N2-dG) causes G-->T versus G-->A mutations based upon a correlation between mutagenesis and molecular modeling results.
A hypothesis for what conformation of the major adduct of (+)-anti-B[a]PDE (N2-dG) causes G-->T versus G-->A mutations based upon a correlation between mutagenesis and molecular modeling results.
复制标题
基于诱变和分子建模结果之间的相关性，假设 ( )-抗 B[a]PDE (N2-dG) 主要加合物的哪种构象会导致 G-->T 与 G-->A 突变。
DOI：
10.1093/carcin/20.1.95
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发表时间：
1999
期刊：
影响因子：
4.7
通讯作者：
Loechler,EL
中科院分区：
文献类型：
--
作者：
Kozack,RE;Shukla,R;Loechler,EL
用分子模拟(模拟退火法)研究了主要的苯并[a]芘(B[a]P)加合物[+ta]-B[a]P-n2-dG(R.E.Kozack和E.L.Loechler，附文)的dsDNA构象。共鉴定了16种构象，并与两个最显著的B[a]P突变，G→T和G→A碱基替换进行了对比分析。八种构象似乎与移码突变更相关，所以它们被排除在外，剩下八种构象如下。两种构象(BPmi5和BPmi3)保留了Watson-Crick G：C碱基对，其加合物的B[a]P部分位于次要凹槽中。两种构象(BPma5和BPma3)具有Hoogsteen取向，其中B[a]P位于主槽中。四种构象发生碱基位移，B[a]P堆积在螺旋中，加合物的DG部分移位到主槽(Gma5和Gma3)或小槽(Gmi5和Gmi3)中。这八种构象中的三种(BPma5、BPma3和Gma3)普遍具有高能量。保持G：C碱基配对潜力的两种构象(BPmi5和BPmi3)可能是非突变的。在剩下的三种构象中，Gmi5的能量相对较低，但被扭曲了。剩余两个碱基移位构象的计算能量与[+ta]-B[a]P-n2-dg的突变之间存在相关性，从而导致假设Gma5导致G→T突变，Gmi3导致G→A突变。Gma5和Gmi3彼此相似，只是DG分别位于主槽和次槽中。讨论了这一假设的初步原理：DNA聚合酶可能被触发遵循不同的诱变途径，这取决于非信息性病变是否有大量突出到大沟或小沟中。还提出了这八种构象之间相互转化的途径，并讨论了它的含义；例如，Gma5和Gmi3之间的相互转化需要四个步骤。
Molecular modeling (simulated annealing) was used to study the conformations in dsDNA of [+ta]-B[a]P–N2-dG (R.E.Kozack and E.L.Loechler, accompanying paper), which is the majorbenzo[a]pyrene (B[a]P) adduct. Sixteen classes of conformations were identified, and are analyzed herein vis-a-vis the two most prominent B[a]P mutations, G→T and G→A base substitutions. Eight conformations seem more relevant to frameshift mutagenesis, so they are excluded, leaving eight conformations as follows. Two conformations (BPmi5 and BPmi3) retain Watson–Crick G:C base pairing having the B[a]P moiety of the adduct in the minor groove. Two conformations (BPma5 and BPma3) have the Hoogsteen orientation with B[a]P in the major groove. Four conformations are base displaced and have B[a]P stacked in the helix with the dG moiety of the adduct displaced into either the major groove (Gma5 and Gma3) or the minor groove (Gmi5 and Gmi3). Three of these eight conformations (BPma5, BPma3 and Gma3) are universally high in energy. The two conformations that retain G:C base pairing potential (BPmi5 and BPmi3) are likely to be non-mutagenic. Of the three remaining conformations, Gmi5 can be relatively low in energy, but is distorted. A correlation exists between the calculated energies for the remaining two base displaced conformations and mutagenesis for [+ta]-B[a]P–N2-dG, leading to the hypothesis that Gma5 is responsible for G→T mutations and Gmi3 is responsible for G→A mutations. Gma5 and Gmi3 resemble each other, except that dG is in the major and minor grooves, respectively. An incipient rationale for this hypothesis is discussed: DNA polymerase might be triggered to follow a different mutagenic pathway depending upon whether a non-informational lesion has bulk protruding into the major or minor groove. A pathway for interconversion between these eight conformations is also proposed and its implications are discussed; e.g. four steps are required to interconvert between Gma5 and Gmi3.