905857-46-7Relevant articles and documents
Discrimination of hairpin polyamides with an α-substituted-γ- aminobutyric acid as a 5′-TG-3′ reader in DNA minor groove
Zhang, Wen,Bando, Toshikazu,Sugiyama, Hiroshi
, p. 8766 - 8776 (2007/10/03)
Pyrrole-imidazole (Py-lm) polyamides containing stereospecifically α-amino- or α-hydroxyl-substituted γ-aminobutyric acid as a 5′-TG-3′ recognition element were synthesized by machine-assisted Fmoc solid-phase synthesis. Their binding properties to predetermined DNA sequences containing a core binding site of 5′-TGCNCA-3′/3′- ACGN′GT-5′ (N·N′ = A·T, T·A, G·C, and C·G) were then systematically studied by surface plasmon resonance (SPR). SPR results revealed that the pairing of stereospecifically α-amino-/α-hydroxyl-substituted γ-aminobutyric acids, (R or S)-α,γ-diaminobutyric acid (γRN or γSN) and (R or S)-α-hydroxyl-γ-aminobutyric acid (γRO or γSO), side-by-side with β-alanine (β) in such polyamides significantly influenced the DNA binding affinity and recognition specificity of hairpin polyamides in the DNA minor groove compared with β/β, β/γ, and γ/β pairings. More importantly, the polyamide Ac-lm-γSO-lmPy-γ-lmPyβPy-β-Dp (β/γSO) favorably binds to a hairpin DNA containing a core binding site of 5′-TGCNCA- 3′/3′-ACGN′GT-5′ (N·N′ = A·T) with dissociation equilibrium constant (KD) of 1.9 × 10-7 M over N·N′ = T·A with KD = 3.7 × 10 -6 M, with a 19-fold specificity. By contrast, Ac-lm-γSN-lmPy- γ-lmPyβPy-β-Dp (β/γSN) binds to the above sequence with N·N′ = A·T with KD = 8.7 × 10 -7 M over N·N′ = T·A with KD = 8.4 × 10-6 M, with a 9.6-fold specificity. The results also show that the stereochemistry of the α-substituent, as well as the α-substituent itself may greatly alter binding affinity and recognition selectivity of hairpin polyamides to different DNA sequences. Further, we carried out molecular modeling studies on the binding by an energy minimization method, suggesting that α-hydroxyl is very close to N3 of the 3′-terminal G to induce the formation of hydrogen bonding between hydroxyl and N3 in the recognition event of the polyamide Ac-lm-γSO-lmPy-γ- lmPyβPy-β-Dp (β/γSO) to 5′-TGCNCA-3′/3′- ACGN′GT-5′ (N·N′ = A·T). Therefore, SPR assays and molecular modeling studies collectively suggest that the (S)-α-hydroxyl-γ-aminobutyric acid (γSO) may act as a 5′-TG-3′ recognition unit.