Sequence-dependent nucleotide dynamics revealed by intercalated ring rotation in DNA-bisnaphthalimide complexes

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Biophysics

Background:

• Bisnaphthalimide intercalators are a class of anti-tumour agents featuring two planar rings linked by a flexible chain.
• These compounds function by intercalating into DNA, suggesting their mechanism of action involves interactions with the DNA duplex.

Purpose of the Study:

• To investigate the dynamic behavior of bisnaphthalimide analogues when complexed with DNA.
• To elucidate the relationship between bisnaphthalimide ring motions, DNA nucleotide dynamics, and drug-DNA binding kinetics.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy was employed to detect and analyze the rotational motions of bisnaphthalimide rings within DNA complexes.
• Comparative analysis of rotation frequencies and activation energies under varying conditions and DNA sequences.

Main Results:

• Bisnaphthalimide intercalator rings undergo 180-degree rotational motions within the DNA duplex, independent of the linker atoms.
• These motions were observed across diverse DNA sequences and lengths, occurring on the millisecond timescale.
• Rotation frequencies varied from 2 to 25 s(-1) at 25°C, influenced by DNA composition and ring size.

Conclusions:

• The observed ring rotations are intrinsic properties of the drug-DNA complex, driven by concerted, sequence-dependent nucleotide movements.
• These dynamics are not linked to drug dissociation and may occur within the DNA duplex.
• The identified nucleotide dynamics are crucial for understanding the binding kinetics of DNA-interacting proteins and drugs.