DNA base sequence specificity through partial intercalation: DFT-D based energy analysis of molecular dynamics...

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• DNA-binding proteins often intercalate hydrophobic side-chains between base pairs, causing DNA bending.
• While some proteins lack sequence specificity, lac repressor exhibits strong operator recognition.
• Lac repressor interacts with DNA minor groove via leucine side-chains and major groove base atoms.

Purpose of the Study:

• To elucidate the role of minor groove intercalation in lac repressor-operator recognition.
• To investigate the energetic and structural consequences of leucine side-chain intercalation into DNA.

Main Methods:

• Extensive quantum chemical calculations.
• Dispersion-corrected density functional theory (DFT).
• Molecular dynamics simulations for snapshot generation.

Main Results:

• Leucine intercalation into DNA is energetically slightly unfavorable.
• The CG/CG-Leucine base-amino acid pair is among the most stable configurations.
• DNA bending induced by intercalation aids protein-DNA interface alignment.

Conclusions:

• A modest sacrifice in binding energy enhances sequence specificity for lac repressor.
• This mechanism may be general for augmenting sequence specificity in other prokaryotic repressors.