Parallel-stranded guanine quadruplex interactions with a copper cationic porphyrin.

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• G-quadruplexes are nucleic acid structures formed by guanine-rich sequences.
• Stabilizing or inducing G-quadruplex formation is a therapeutic strategy.
• CuTMpyP4 is a copper derivative of a porphyrin ligand investigated for G-quadruplex interactions.

Purpose of the Study:

• To investigate the binding interactions between CuTMpyP4 and parallel-stranded G-quadruplexes formed by d(T(4)G(4)T(4)) and d(T(4)G(8)T(4)).
• To characterize the binding stoichiometry, affinity, and mode of interaction.

Main Methods:

• Absorption titration spectroscopy to monitor spectral changes upon binding.
• Scatchard and McGhee-von Hippel models for binding affinity and site size determination.
• Continuous variation analysis for binding stoichiometry.
• Induced emission spectroscopy and Electron Paramagnetic Resonance (EPR) spectroscopy for binding mode elucidation.

Main Results:

• CuTMpyP4 exhibits bathochromic and hypochromic shifts in its Soret band upon binding to G-quadruplexes, with larger effects for longer oligonucleotides.
• Binding constants varied significantly with oligonucleotide length and model used, indicating complex interactions.
• Binding stoichiometry was determined as 2:1 for CuTMpyP4:(1)(4) and 3:1 for CuTMpyP4:(3)(4).
• Spectroscopic data suggest external stacking of CuTMpyP4 at the ends of the guanine tracts, with potential intercalation for the longer G-quadruplex.

Conclusions:

• CuTMpyP4 interacts with parallel-stranded G-quadruplexes through external stacking and potentially intercalation.
• The binding mode and affinity are influenced by the length of the G-quadruplex.
• These findings contribute to understanding G-quadruplex-ligand interactions for potential therapeutic applications.