Sequence and supercoiling-dependent effects on the structural dynamics of DNA minicircles

Area of Science:

• Biophysics
• Molecular Biology
• Computational Biology

Background:

• DNA supercoiling, measured by superhelical density, is crucial for regulating gene expression.
• DNA can dissipate mechanical stress by forming local denaturation or defective states.
• These DNA motifs are recognized by proteins like transcription factors and nucleases.

Purpose of the Study:

• To investigate how DNA sequence and superhelical density affect the structural dynamics of a DNA minicircle.
• To understand the formation and stability of denaturation bubbles in response to topological stress.
• To explore the role of sequence flexibility in stabilizing these DNA defects.

Main Methods:

• Classical molecular dynamics simulations were performed.
• The coarse-grained oxDNA force field was utilized.
• A 672-bp DNA minicircle was modeled and simulated.

Main Results:

• Undercoiled DNA minicircles exhibited stable, broad denaturation bubbles.
• These bubbles preferentially formed at flexible nucleotide sequences.
• The presence of these defects significantly influenced the DNA molecule's dynamics, acting as pinning sites.

Conclusions:

• Superhelical density and sequence composition dictate DNA structural evolution and defect formation.
• Denaturation bubbles in undercoiled DNA are stable and sequence-dependent.
• Synthetic DNA mismatches can effectively mimic these sequence-independent defects, offering potential for DNA manipulation.