Peptide bis-intercalator binds DNA via threading mode with sequence specific contacts in the major groove

Area of Science:

• Chemical Biology
• Molecular Biology
• Drug Discovery

Background:

• Previously developed DNA polyintercalators using 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) units linked by peptides.
• Demonstrated that peptide tether modifications yield novel DNA binding specificities.
• Focused on Compound 1, an NDI bis-intercalator with a gly-gly-gly-lys peptide linker, for detailed study.

Purpose of the Study:

• To elucidate the DNA binding mode of Compound 1.
• To understand the sequence-specific recognition mechanism of NDI bis-intercalators.
• To explore the role of the peptide linker in DNA interaction.

Main Methods:

• 1H-NMR spectroscopy to determine the structure of Compound 1 bound to d(CGGTACCG)(2).
• DNAse I footprinting assays on related analogs.
• Analysis of steric and electrostatic interactions.

Main Results:

• Confirmed a threading intercalation mode with four base pairs separating the NDI units.
• NMR data revealed specific binding to the d(CGGTACCG) sequence.
• Identified peptide linker contacts within the major groove floor as critical for specificity.

Conclusions:

• The modular NDI-based polyintercalator system allows for tuning of DNA binding specificity.
• Structural insights enable the design of improved or novel DNA-binding compounds.
• Facilitates the development of longer polyintercalators for recognizing extended DNA sequences and accessing both DNA grooves.