Marshall's nucleic acid: From double-helical structure to a potent intercalator

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Deoxyribonucleic acid (DNA) is a key genetic material and a significant drug target.
• Modified nucleotides are actively researched for therapeutic applications, with several FDA-approved drugs.
• Altering the DNA backbone is a strategy to develop novel nucleic acid-based therapeutics.

Purpose of the Study:

• To investigate the structural stability of marshall's nucleic acid (MNA) with a neutral backbone.
• To compare MNA's structural properties with regular DNA.
• To evaluate MNA-based oligonucleotides as potential DNA-targeting ligands.

Main Methods:

• Gaussian accelerated molecular dynamics simulations (1 μs) were used to analyze MNA structures in aqueous media.
• The study compared MNA with a neutral backbone to control DNA with a negatively charged backbone.
• MNA-based single-stranded dinucleotides were tested as intercalating ligands for B-DNA.

Main Results:

• Unmodified MNA showed partial denaturation, but conformationally locked MNA maintained a stable double-helical structure.
• MNA exhibited a similar helical rise to DNA but a significantly different helical twist (~56° for MNA vs. ~35° for DNA).
• MNA-based dinucleotides acted as effective intercalating ligands, unwinding B-DNA and demonstrating high binding affinities.

Conclusions:

• Marshall's nucleic acid (MNA) can form stable double-helical structures with unique conformational properties.
• MNA-based molecules show promise as novel agents for DNA-targeted drug discovery.
• Small MNA fragments may serve as effective ligands for therapeutic intervention in DNA-related diseases.