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Berenil Binds Tightly to Parallel and Mixed Parallel/Antiparallel G-Quadruplex Motifs with Varied Thermodynamic Signatures
ACS Omega ( IF 3.7 ) Pub Date : 2018-09-21 00:00:00 , DOI: 10.1021/acsomega.8b01621 Clinton G. Mikek 1, 2 , Savannah J. West 3 , J. Cole Gwin 3 , Neetu Dayal 1, 2 , Herman O. Sintim 1, 2 , Edwin A. Lewis 3
ACS Omega ( IF 3.7 ) Pub Date : 2018-09-21 00:00:00 , DOI: 10.1021/acsomega.8b01621 Clinton G. Mikek 1, 2 , Savannah J. West 3 , J. Cole Gwin 3 , Neetu Dayal 1, 2 , Herman O. Sintim 1, 2 , Edwin A. Lewis 3
Affiliation
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Diminazene, DMZ, (or berenil) has been reported as a tight binder of G-quadruplexes. G-Quadruplex structures are often located in the promotor regions of oncogenes and may play a regulatory role in gene expression based on the stability of the folding topology. In this study, attempts have been made to characterize the specificity of DMZ binding toward multiple G-quadruplex topologies or foldamers. Mutant sequences of the G-quadruplex forming promotor regions of several oncogenes were designed to exhibit restricted loop lengths and folding topologies. Circular dichroism was used to confirm the quadruplex topology of mutant BCL2, KRAS, and c-MYC sequences, human telomere (Na+ and K+) G-quadruplexes and their complexes with DMZ and analogs thereof. Isothermal titration calorimetry was used to generate a complete thermodynamic profile (ΔG, ΔH, −TΔS) for the formation of DMZ and analog complexes with the target G-quadruplexes. DMZ binds to parallel and/or mixed parallel/antiparallel quadruplex DNA motifs with stoichiometries up to 8:1 and via three binding modes with varying affinities. In the case of the parallel G-quadruplexes, with the exception of the long-looped c-MYC mutant, the highest affinity binding event (mode 1) is driven by enthalpy. DMZ binding to the long-looped c-MYC mutant exhibits a very favorable entropy change in addition to a moderately favorable enthalpy change. Mode 1 binding to the antiparallel and mixed parallel/antiparallel hTel quadruplexes is also driven by favorable enthalpy changes. In all cases, the intermediate DMZ affinity binding (mode 2) is driven almost entirely by entropy, with small or unfavorable enthalpic contributions. The weakest binding event (mode 3) is also entropically driven with small or moderate enthalpic contributions.
中文翻译：
Berenil与具有各种热力学特征的平行和混合平行/反平行G-四联体基团紧密结合
据报道，地那敏，DMZ（或苯甲腈）是G-四链体的紧密结合剂。G-四链体结构通常位于癌基因的启动子区域，并可能基于折叠拓扑的稳定性在基因表达中发挥调控作用。在这项研究中，已尝试表征DMZ对多种G-四链体拓扑或折叠剂的结合特异性。G-四链体形成几个致癌基因的启动子区域的突变序列被设计为显示出受限的环长度和折叠拓扑。圆二色性用于确认突变型BCL2，KRAS和c-MYC序列，人端粒（Na +和K +G-四链体及其与DMZ及其类似物的复合体。等温滴定量热法用于产生一个完整的热力学轮廓（Δ G ^，Δ ħ， - Ť Δ小号）与目标G-四链体形成DMZ和类似物复合体。DMZ以化学计量比高达8：1并通过具有不同亲和力的三种结合模式与平行和/或混合的平行/反平行四链体DNA基序结合。在平行的G-四链体的情况下，除了长环c-MYC突变体以外，最高的亲和力结合事件（模式1）是由焓驱动的。DMZ与长环c-MYC突变体的结合除了表现出适度的焓变外，还表现出非常有利的熵变。绑定到反平行和混合的平行/反平行hTel四链体的模式1也受到有利的焓变化的驱动。在所有情况下，中间DMZ亲和力结合（模式2）几乎完全由熵驱动，焓贡献很小或不利。
更新日期：2018-09-21
中文翻译：
Berenil与具有各种热力学特征的平行和混合平行/反平行G-四联体基团紧密结合
据报道，地那敏，DMZ（或苯甲腈）是G-四链体的紧密结合剂。G-四链体结构通常位于癌基因的启动子区域，并可能基于折叠拓扑的稳定性在基因表达中发挥调控作用。在这项研究中，已尝试表征DMZ对多种G-四链体拓扑或折叠剂的结合特异性。G-四链体形成几个致癌基因的启动子区域的突变序列被设计为显示出受限的环长度和折叠拓扑。圆二色性用于确认突变型BCL2，KRAS和c-MYC序列，人端粒（Na +和K +G-四链体及其与DMZ及其类似物的复合体。等温滴定量热法用于产生一个完整的热力学轮廓（Δ G ^，Δ ħ， - Ť Δ小号）与目标G-四链体形成DMZ和类似物复合体。DMZ以化学计量比高达8：1并通过具有不同亲和力的三种结合模式与平行和/或混合的平行/反平行四链体DNA基序结合。在平行的G-四链体的情况下，除了长环c-MYC突变体以外，最高的亲和力结合事件（模式1）是由焓驱动的。DMZ与长环c-MYC突变体的结合除了表现出适度的焓变外，还表现出非常有利的熵变。绑定到反平行和混合的平行/反平行hTel四链体的模式1也受到有利的焓变化的驱动。在所有情况下，中间DMZ亲和力结合（模式2）几乎完全由熵驱动，焓贡献很小或不利。
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