Ogbonna Edwin N, Paul Ananya, Farahat Abdelbasset A, Terrell J Ross, Mineva Ekaterina, Ogbonna Victor, Boykin David W, Wilson W David
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303-3083, United States.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
ACS Bio Med Chem Au. 2023 Apr 5;3(4):335-348. doi: 10.1021/acsbiomedchemau.3c00002. eCollection 2023 Aug 16.
The rational design of small molecules that target specific DNA sequences is a promising strategy to modulate gene expression. This report focuses on a diamidinobenzimidazole compound, whose selective binding to the minor groove of AT DNA sequences holds broad significance in the molecular recognition of AT-rich human promoter sequences. The objective of this study is to provide a more detailed and systematized understanding, at an atomic level, of the molecular recognition mechanism of different AT-specific sequences by a rationally designed minor groove binder. The specialized method of X-ray crystallography was utilized to investigate how the sequence-dependent recognition properties in general, A-tract, and alternating AT sequences affect the binding of diamidinobenzimidazole in the DNA minor groove. While general and A-tract AT sequences give a narrower minor groove, the alternating AT sequences intrinsically have a wider minor groove which typically constricts upon binding. A strong and direct hydrogen bond between the N-H of the benzimidazole and an H-bond acceptor atom in the minor groove is essential for DNA recognition in all sequences described. In addition, the diamidine compound specifically utilizes an interfacial water molecule for its DNA binding. DNA complexes of AATT and AAAAAA recognition sites show that the diamidine compound can bind in two possible orientations with a preference for water-assisted hydrogen bonding at either cationic end. The complex structures of AAATTT, ATAT, ATATAT, and AAAA are bound in a singular orientation. Analysis of the helical parameters shows a minor groove expansion of about 1 Å across all the nonalternating DNA complexes. The results from this systematic approach will convey a greater understanding of the specific recognition of a diverse array of AT-rich sequences by small molecules and more insight into the design of small molecules with enhanced specificity to AT and mixed DNA sequences.
设计靶向特定DNA序列的小分子是一种很有前景的调控基因表达的策略。本报告聚焦于一种二脒基苯并咪唑化合物，其对AT DNA序列小沟的选择性结合在富含AT的人类启动子序列的分子识别中具有广泛意义。本研究的目的是在原子水平上更详细、系统地了解一种合理设计的小沟结合剂对不同AT特异性序列的分子识别机制。利用X射线晶体学的专门方法来研究一般的、A序列片段以及交替AT序列中依赖序列的识别特性如何影响二脒基苯并咪唑在DNA小沟中的结合。虽然一般的和A序列片段的AT序列会使小沟变窄，但交替AT序列本身具有较宽的小沟，其在结合时通常会收缩。苯并咪唑的N-H与小沟中的氢键受体原子之间形成的强而直接的氢键对于所有所述序列的DNA识别至关重要。此外，二脒化合物在其DNA结合中特别利用了一个界面水分子。AATT和AAAAAA识别位点的DNA复合物表明，二脒化合物可以以两种可能的方向结合，在任一阳离子末端更倾向于水辅助氢键。AAATTT、ATAT、ATATAT和AAAA的复合物结构以单一方向结合。螺旋参数分析表明，在所有非交替DNA复合物中，小沟约扩展1 Å。这种系统方法的结果将使人们对小分子对多种富含AT序列的特异性识别有更深入的理解，并对设计对AT和混合DNA序列具有更高特异性的小分子有更多的见解。
