Recognition of base mismatches in DNA by 5,6-chrysenequinone diimine complexes of rhodium(III): A proposed mechanism for preferential binding in destabilized regions of the double helix
Recognition of base mismatches in DNA by 5,6-chrysenequinone diimine complexes of rhodium(III): A proposed mechanism for preferential binding in destabilized regions of the double helix
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DOI：
10.1021/bi9927033
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发表时间：
2000-05-23
期刊：
影响因子：
2.9
通讯作者：
Barton, JK
中科院分区：
文献类型：
--
作者：
Jackson, BA;Barton, JK
铑（III）的5，6-蒽醌二亚胺（chrysi）配合物已被证明是DNA中错配碱基对的通用和特异性识别剂。这些化合物的设计是基于这样的假设，即空间膨胀的chrysi配体（其应该太宽而不能容易地嵌入B-DNA）将优先结合在碱基错配附近的DNA螺旋的不稳定区域中。在这项工作中，这种识别假设进行了全面的探讨。通过比较配合物[Rh（bpy）（2）（chrysi）]（3+）与非空间位阻类似物[Rh（bpy）（2）（phi）]（3+）（phi = 9，10-菲醌二亚胺）的识别模式，证明chrysi配体不利于与B-DNA结合，并产生错配选择性。在恒定和可变序列背景下，使用光裂解测定法检查[Rh（byp）（2）（chrysi）]（3+）的错配识别，表明碱基错配的识别受到错配使DNA螺旋不稳定的数量的影响。已通过定量光裂解滴定和产率值确定了一系列错配位点处铑配合物的热力学结合常数，产率值从1 x 10（6）到20 x 10（6）M-1不等。这些错配特异性结合亲和力与热力学不稳定的独立测量相关，支持螺旋不稳定是决定金属络合物对错配位点的结合亲和力的因素的假设。尽管不是[Rh（bpy）（2）（chrysi）]（3+）与错配位点结合的唯一因素，但提出了一种模型，其中螺旋不稳定作为“门”，允许空间要求高的嵌入剂进入碱基堆叠。
5,6-Chrysenequinone diimine (chrysi) complexes of rhodium(III) have been shown to be versatile and specific recognition agents for mismatched base pairs in DNA. The design of these compounds was based on the hypothesis that th esterically expansive chrysi ligand, which should be too wide to readily intercalate into B-DNA, would bind preferentially in the destabilized regions of the DNA helix near base mismatches. In this work, this recognition hypothesis is comprehensively explored. Comparison of the recognition patterns of the complex [Rh(bpy)(2)(chrysi)](3+) with a nonsterically demanding analogue, [Rh(bpy)(2)(phi)](3+) (phi = 9,10-phenanthrenequinone diimine), demonstrates that the chrysi ligand does disfavor binding to B-DNA and generate mismatch selectivity. Examination of mismatch recognition by [Rh(byp)(2)(chrysi)](3+) in both constant and variable sequence contexts using photocleavage assays indicates that the recognition of base mismatches is influenced by the amount that a mismatch thermodynamically destabilizes the DNA helix. Thermodynamic binding constants for the rhodium complex at a range of mismatch sites have been determined by quantitative photocleavage titration and yield values which vary from 1 x 10(6) to 20 x 10(6) M-1. These mismatch-specific binding affinities correlate with independent measurements of thermodynamic destabilization, supporting the hypothesis that helix destabilization is a factor determining the binding affinity of the metal complex for the mismatched site. Although not the only factor involved in the binding of [Rh(bpy)(2)(chrysi)](3+) to mismatch sites, a model is proposed where helix destabilization acts as the "door" which permits access of the sterically demanding intercalator to the base stack.