Journal
ORGANIC & BIOMOLECULAR CHEMISTRY
Volume 15, Issue 46, Pages 9880-9888Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c7ob02513k
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Funding
- National Institutes of Health (NIH) USA [GM111749]
- UMSL College of Arts and Sciences and Office of Research Administration
- NSF [0959360]
- Danforth Plant Sciences Center [NSF DBI 0922879]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [0959360] Funding Source: National Science Foundation
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Minor-groove binding hairpin polyamides (PAs) bind specific DNA sequences. Synthetic modifications can improve PA-DNA binding affinity and include flexible modules, such as beta-alanine (beta) motifs to replace pyrroles (Py), and increasing compound charge using N-terminal cationic substituents. To better understand the variations in kinetics and affinities caused by these modifications on PA-DNA interactions, a comprehensive set of PAs with different numbers and positions of beta and different types of N-cationic groups was systematically designed and synthesized to bind their cognate sequence, the lambda B motif. The lambda B motif is also a strong binding promoter site of the major groove targeting transcription factor PU.1. The PA binding affinities and kinetics were evaluated using a spectrum of powerful biophysical methods: thermal melting, biosensor surface plasmon resonance and circular dichroism. The results show that beta inserts affect PA-DNA interactions in a number and position dependent manner. Specifically, a beta replacement between two imidazole heterocycles (Im beta Im) generally strengthens binding. In addition, N-terminal cationic groups can accelerate the association between PA and DNA, but the bulky size of TMG can cause steric hindrance and unfavourable repulsive electrostatic interactions in some PAs. The future design of stronger binding PA requires careful combination of beta s and cationic substituents.
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