Recognition by Nonaromatic and Stereochemical Subunit-Containing Polyamides of the Four Watson-Crick Base Pairs in the DNA Minor Groove

• Published in: Chembiochem : a European journal of chemical biology Vol. 13; no. 9; pp. 1366 - 1374
• Main Authors: Zhang, Hong-Fei, Wu, Yan-Ling, Jiang, Shi-Kun, Wang, Pu, Sugiyama, Hiroshi, Chen, Xing-Lai, Zhang, Wen, Ji, Yan-Juan, Guo, Chuan-Xin
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 18.06.2012; WILEY‐VCH Verlag
• Subjects: aminocyclopentane carboxylic acid; Base Pairing; Base Sequence; DNA - chemistry; DNA - genetics; DNA - metabolism; DNA recognition; Inverted Repeat Sequences; Kinetics; Nylons - chemistry; Nylons - metabolism; polyamides; Stereoisomerism; Substrate Specificity; surface plasmon resonance; Thermodynamics; thymine
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201200137

In order to develop an optimal subunit as a T‐recognition element in hairpin polyamides, 15 novel chirality‐modified polyamides containing (R)‐α,β‐diaminopropionic acid (Rβ α‐NH 2), (S)‐α,β‐diaminopropionic acid (Sβ α‐NH 2), (1R,3S)‐3‐aminocyclopentanecarboxylic acid (RSCp), (1S,3R)‐3‐amino‐cyclopentanecarboxylic acid (RSCp), (1R,3R)‐3‐aminocyclopentanecarboxylic acid (RRCp) and (1S,3S)‐3‐amino‐cyclopentanecarboxylic acid (SSCp) residues were synthesized. Their binding characteristics to DNA sequences 5′‐TGCNCAT‐3′/3′‐ACGN′GTA‐5′ (N⋅N′=A⋅T, T⋅A, G⋅C and C⋅G) were systemically studied by surface plasmon resonance (SPR) and molecular simulation (MSim) techniques. SPR showed that polyamide 4, AcIm‐Sβ α‐NH 2‐ImPy‐γ‐ImPy‐β‐Py‐βDp (β/Sβ α‐NH 2 pair), bound to a DNA sequence containing a core binding site of 5′‐TGCACAT‐3′ with a dissociation equilibrium constant (KD) of 4.5×10−8 m. This was a tenfold improvement in specificity over 5′‐TGCTCAT‐3′ (KD=4.5×10−7 M). MSim studies supported the SPR results. More importantly, for the first time, we found that chiral 3‐aminocyclopentanecarboxylic acids in polyamides can be employed as base readers with only a small decrease in binding affinity to DNA. In particular, SPR showed that polyamide 9 (RRCp/β pair) had a 15‐fold binding preference for 5′‐TGCTCAT‐3′ over 5′‐TGCACAT‐3′. A large difference in standard free energy change for A⋅T over T⋅A was determined (ΔΔGo=5.9 kJ mol−1), as was a twofold decrease in interaction energy by MSim. Moreover, a 1:1 stoichiometry (9 to 5′‐TGCTCAT‐3′/3′‐ACGAGTA‐5′) was shown by MSim to be optimal for the chiral five‐membered cycle to fit the minor groove. Collectively, the study suggests that the (S)‐α‐amino‐β‐aminopropionic acid and (1R,3R)‐3‐aminocyclopentanecarboxylic acid can serve as a T‐recognition element, and the stereochemistry and the nature of these subunits significantly influence binding properties in these recognition events. Subunit (1R,3R)‐3‐aminocyclopentanecarboxylic acid broadens our scope to design novel polyamides. Groovy recognition: A chiral nonaromatic five‐membered cyclic subunit, (1R,3R)‐3‐aminocyclopentane carboxylic acid, serves as a DNA thymine‐specific recognition element when incorporated into polyamides, in minor‐groove sequence‐specific recognition events. The results broaden our understanding and will help in the design of novel polyamides that include T‐recognition preference.