On the pairing rules for recognition in the minor groove of DNA by pyrrole-imidazole polyamides
On the pairing rules for recognition in the minor groove of DNA by pyrrole-imidazole polyamides
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DOI：
10.1016/s1074-5521(97)90243-x
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发表时间：
1997-08-01
影响因子：
--
通讯作者：
Dervan, PB
中科院分区：
文献类型：
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作者：
White, S;Baird, EE;Dervan, PB
背景：靶向具有高亲和力和高特异性的预定DNA序列的细胞通透性小分子具有控制基因表达的潜力，已开发出一种二进制代码来关联DNA序列与DNA小沟槽中N-甲基吡咯(Py)和N-甲基咪唑(Im)羧胺之间的并列配对，我们着手确定Im/Py，Py/Im，Im/Im和Py/Py对的相对能量。结果：测定了一系列四个六环发夹聚酰胺在两个五碱基位置上的平衡结合常数，为了测试中心位置上与G.C和A.T碱基对相对的四个芳香族氨基酸对的相对能量，我们观察到G.C碱基对有效地靶向了Im/Py，而不是Py/Im，Py/Py，或Im/Im。A.T碱基对有效地被Py/Py靶向，而不是Im/Py，Py/Im，或Im/Im。结论：Im/Im配对对于识别A.T和G.C.是不受欢迎的。这种特异性将对小沟中可用于未连接的二聚体的不受欢迎的滑动基序产生重要的限制。因此，将创建基线能量参数，利用当前用于双螺旋DNA特定分子识别的配对规则的可预测性，将指导进一步用于DNA识别的第二代聚酰胺设计。
Background: Cell-permeable small molecules that target predetermined DNA sequences with high affinity and specificity have the potential to control gene expression, A binary code has been developed to correlate DNA sequence with side-by-side pairings between N-methylpyrrole (Py) and N-methylimidazole (Im) carboxamides in the DNA minor groove, We set out to determine the relative energetics of pairings of Im/Py, Py/Im, Im/Im, and Py/Py for targeting G.C and A.T base pairs. A key specificity issue, which has not been previously addressed, is whether an Im/Im pair is energetically equivalent to an Im/Py pair for targeting G.C base pairs.Results: Equilibrium association constants were determined at two five-basepair sites for a series of four six-ring hairpin polyamides, in order to test the relative energetics of the four aromatic amino-acid pairings opposite G.C and A.T base pairs in the central position, We observed that a G.C base pair was effectively targeted with Im/Py but not Py/Im, Py/Py, or Im/Im. The A.T base pair was effectively targeted with Py/Py but not Im/Py, Py/Im, or Im/Im.Conclusions: An Im/Im pairing is energetically disfavored for the recognition of both A.T and G.C. This specificity will create important limitations on undesirable slipped motifs that are available for unlinked dimers in the minor groove. Baseline energetic parameters will thus be created which, using the predictability of the current pairing rules for specific molecular recognition of double-helical DNA, will guide further second-generation polyamide design for DNA recognition.