Dissecting Dynamic and Hydration Contributions to Sequence-Dependent DNA Minor Groove Recognition

Area of Science:

• Molecular Biology
• Biophysics
• Medicinal Chemistry

Background:

• Sequence selectivity is crucial for DNA-binding ligands.
• DB1976 is a promising therapeutic agent for various diseases.
• Understanding DB1976's DNA binding is essential for its development.

Purpose of the Study:

• Investigate the binding and volumetric properties of DB1976.
• Determine how DB1976 interacts with different DNA sequences.
• Elucidate the relationship between binding affinity, dynamics, and hydration.

Main Methods:

• Evaluated DB1976 binding to three distinct dodecameric DNA duplexes.
• Measured partial molar volumes and hydration changes.
• Performed explicit-atom molecular dynamics simulations.
• Experimentally validated hydration effects using salt-dependent assays.

Main Results:

• DB1976 binding affinity varied over three orders of magnitude across DNA sequences.
• Changes in partial molar volumes did not correlate directly with binding affinity.
• Molecular dynamics revealed sequence-dependent perturbations in DNA dynamics and hydration.
• Both high- and low-affinity binding involved favorable hydration release.
• Ligand binding influenced DNA dynamics at both internal sites and termini.

Conclusions:

• DB1976 exhibits sequence-specific DNA binding with distinct interaction modes.
• Hydration dynamics play a significant role in DB1976-DNA complex formation.
• Sequence-dependent dynamic effects along DNA can influence ligand efficacy.
• Findings provide insights into DB1976's mechanism of action and therapeutic potential.