NMR determination of the conformation of a trimethylene interstrand cross-link in an oligodeoxynucleotide duplex containing a 5′-d(GpC) motif
NMR determination of the conformation of a trimethylene interstrand cross-link in an oligodeoxynucleotide duplex containing a 5′-d(GpC) motif
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DOI：
10.1021/ja0207798
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发表时间：
2003-01-08
影响因子：
15
通讯作者：
Harris, TM
中科院分区：
文献类型：
--
作者：
Dooley, PA;Zhang, MZ;Harris, TM
DNA中的丙二醛链间交联物对5‘-d(CpG)序列表现出强烈的选择性。交联剂是不稳定的，三亚甲基交联剂已被用作结构研究的替代物。先前利用模拟退火法通过核磁共振光谱和分子动力学对序列5‘-d(CpG)中的5’-d(CpG)交联链的结构进行了研究，其中G*是修饰的核苷酸，结果表明鸟嘌呤残基和系绳大致位于一个平面上，这样三亚甲基系链和可能的丙二醛系链可以在不破坏双链结构的情况下被调节[Dooley等人]。J.Am Chem。SoC。2001、123、1730-1739]。现在已经使用反向序列在GPC基序中研究了三亚甲基交联物。该结构缺乏5‘-d(CpG)序列的平面性，并且围绕三亚甲基交联物倾斜。熔融研究表明，三亚甲基交联物在GPC基序中的热力学稳定性低于5-d(CpG)。此外，由于GPC交联物的平面性不足，使得丙二醛不能以等位异构体取代丙二醛。类似的论点可以用来解释5‘-d(CpG)对丙烯醛的链间交联性的偏好。
Malondialdehyde interstrand cross-links in DNA show strong preference for 5'-d(CpG) sequences. The cross-links are unstable and a trimethylene cross-link has been used as a surrogate for structural studies. A previous structural study of the 5'-d(CpG) cross-link in the sequence 5'-d(AGGCG*CCT), where G* is the modified nucleotide, by NMR spectroscopy and molecular dynamics using a simulated annealing protocol showed the guanine residues and the tether lay approximately in a plane such that the trimethylene tether and probably the malondialdehyde tether, as well, could be accommodated without major disruptions of duplex structure [Dooley et al. J. Am Chem. Soc. 2001, 123, 1730-1739]. The trimethylene cross-link has now been studied in a GpC motif using the reverse sequence. The structure lacks the planarity seen with the 5'-d(CpG) sequence and is skewed about the trimethylene cross-link. Melting studies indicate that the trimethylene cross-link is thermodynamically less stable in the GpC motif than in the 5-d(CpG). Furthermore, lack of planarity of the GpC cross-link precludes making an isosteric replacement of the trimethylene tether by malondialdehyde. A similar argument can be used to explain the 5'-d(CpG) preference for interchain cross-linking by acrolein.