MOLECULAR DOCKING INVESTIGATION OF A DNA-RECOGNIZING MOLECULE AT THE ΚB DNA REGION

Polyamide-based molecules have attracted considerable interest as sequence-recognizing agents that interact with biologically relevant DNA regions. In this study, we investigated the potential interaction of previously synthesized and characterized polyamide 6 (PA6) with the κB DNA region associated with the nuclear factor-κB (NF-κB) complex using molecular docking. The previously reported structural identity of PA6 was supported by spectroscopic and chromatographic characterization. We also evaluated the physicochemical and pharmacokinetic properties of PA6 using SwissADME.
We performed molecular docking against the crystallographic NF-κB–DNA complex (PDB ID: 1LE5), focusing the docking region on the central κB DNA sequence. The initial docking calculation generated 20 poses with predicted affinities ranging from −6.117 to −5.710 kcal mol⁻¹, with the highest-ranked pose at −6.117 kcal mol⁻¹. Several closely related poses showed RMSD values of approximately 2.29–2.67 Å, while alternative poses with similar docking scores displayed substantially different orientations. Detailed interaction analysis of the highest-ranked pose identified three conventional hydrogen bonds involving DA5, DA7, and DT8, together with additional contacts involving neighboring κB nucleotides. The interaction pattern was predominantly directed toward nucleobase atoms accessible from the major groove, supporting a major-groove-oriented recognition mode rather than a minor-groove binding mode.
To assess the robustness of the docking search, we performed an independent calculation using a different random seed. This calculation produced a best predicted affinity of −6.329 kcal mol⁻¹ and generated two hydrogen bonds involving DG3 and DC22. Although the corresponding top-ranked poses differed substantially in their overall orientation (cross-run RMSD = 7.929 Å), both calculations localized PA6 within the κB DNA region. They identified nucleobase-directed interactions in the same general sequence environment. Collectively, the results indicate that PA6 can adopt multiple favorable docking orientations within the κB DNA region while retaining recurrent interactions with DNA bases. These findings provide structural insight into PA6's potential DNA-recognition properties and establish a computational basis for further experimental investigation of its interaction with κB DNA.