The triplex-hairpin transition in cytosine-rich DNA

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• DNA can form complex secondary structures beyond the canonical double helix.
• Intramolecular triplexes are formed by single-stranded DNA folding, stabilized by Hoogsteen base pairing.
• Protonation of cytosine bases is crucial for triplex formation at acidic pH.

Purpose of the Study:

• To theoretically investigate the energetics and mechanism of the transition between a DNA hairpin duplex and an intramolecular triplex.
• To understand the role of pH-dependent protonation in DNA structural transitions.
• To explore the coupling between ionization and folding in cytosine-rich triplexes.

Main Methods:

• Applied the Bashford-Karplus model to calculate titration curves for duplex and triplex conformations.
• Utilized a two-state model to study equilibrium properties of the triplex-hairpin transition.
• Performed molecular dynamics simulations with the AMBER 6.0 package and ff94 force field.
• Integrated Poisson-Boltzmann calculations with molecular dynamics to track protonation events.

Main Results:

• The study successfully modeled the thermodynamics of protonation-deprotonation driving the folding-unfolding of the DNA oligomer.
• Molecular dynamics simulations revealed a sequence of elementary protonation steps during the folding/unfolding transition.
• A strong coupling between ionization and folding was identified as critical for cytosine-rich triple-helical triplexes.

Conclusions:

• The transition between DNA hairpin and triplex conformations is thermodynamically governed by pH-dependent protonation.
• The folding/unfolding pathway involves a dynamic interplay of protonation and structural changes.
• Understanding this ionization-folding coupling is essential for designing and utilizing DNA triplex structures.