Free Energy Landscape between Watson-Crick to Hoogsteen Base Pairing Transitions

Area of Science:

• Molecular Biology
• Biophysics
• Computational Chemistry

Background:

• DNA base pairing is fundamental to genetic information storage and transfer.
• Alternative base pairing modes, like Hoogsteen (HG), can occur alongside standard Watson-Crick (WC) pairing.
• The influence of proteins on WC-HG base pair transitions is not well understood.

Purpose of the Study:

• To investigate the free energy landscape of WC-HG base pair transitions in DNA.
• To develop and validate a computational protocol for studying base pair transitions using well-tempered metadynamics.
• To determine the effect of protein presence on the stability and transition dynamics of WC and HG base pairs.

Main Methods:

• Employed the well-tempered metadynamics (WT-MetaD) simulation method.
• Utilized the glycosidic angle (χ) as a collective variable (CV) to define the transition pathway.
• Validated the protocol against existing experimental and simulation data for naked DNA.

Main Results:

• The energy barrier for the Watson-Crick (WC) to Hoogsteen (HG) base pair transition significantly decreases to ~8 kcal/mol in the presence of proteins, compared to naked DNA.
• In the presence of proteins, HG base pairs become approximately 4.0 kcal/mol more stable than WC base pairs.
• The reverse HG to WC transition exhibits an increased energy barrier of ~12 kcal/mol, with HG pairs remaining ~3 kcal/mol more stable.

Conclusions:

• Protein binding can significantly alter the energetics of DNA base pair transitions.
• The study provides a validated computational framework for investigating protein-DNA interactions at the base pair level.
• These findings have implications for understanding DNA structural dynamics and protein recognition mechanisms.