X-ray Structure Characterization of the Selective Recognition of AT Base Pair Sequences

Abstract

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.

Synthesis, Structural Investigations, DNA/BSA Interactions, Molecular Docking Studies, and Anticancer Activity of a New 1,4-Disubstituted 1,2,3-Triazole Derivative

“…We achieved more accurate results with the XP3 method, wherein the enhanced planarity of conjugated pi groups was implemented. In docking, we used crystal structures with PDB IDs: 1Z3F, 3FT6, 1D30, and 8EC1 . The first two structures can be given as examples of intercalation, whereas the last two represented the groove binding.…”

“…In docking, we used crystal structures with PDB IDs: 1Z3F , 87 3FT6 , 88 1D30 , 89 and 8EC1 . 90 The first two structures can be given as examples of intercalation, whereas the last two represented the groove binding. We performed docking using the OPLS3e force field 91 and described the box dimensions to include the whole DNA present in the crystal structures studied.…”

Exploration of the Character Representation of DNA Chiral Conformations and Deformations via a Curved Surface Discrete Frenet Frame

“…The structure of B-DNA was obtained from the PDB database. The PDB ids used in this article are shown in Supplementary Table S1 [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Because of missing Z-DNA experimental structures with sufficient length (containing at least one helical period), the structure of Z-DNA was conducted by the homology model method (Accelrys.…”

“…Supplementary Materials: The supporting information can be downloaded at: https://www.mdpi.com/ article/10.3390/ijms25010004/s1. References [27][28][29][30][31][32][33][34][35][36][39][40][41][42][43] are cited in the supplementary materials.…”

“…The supporting information can be downloaded at: . References [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , 40 , 41 , 42 , 43 ] are cited in the supplementary materials.…”