Structural insights into the effect of isonucleosides on B-DNA duplexes using molecular-dynamics simulations

Area of Science:

• Structural biology
• Computational chemistry
• Molecular modeling

Background:

• Isonucleosides are analogs of natural nucleosides.
• Understanding their structural impact on DNA is crucial for developing novel nucleic acid technologies.

Purpose of the Study:

• To investigate the structural conformations of DNA duplexes containing incorporated isonucleosides.
• To analyze the effects of isonucleosides on DNA stability and binding properties.

Main Methods:

• Unrestrained molecular-dynamics (MD) simulations using the AMBER force field and particle mesh Ewald method.
• Explicit solvent and periodic boundary conditions were employed for 18-mer DNA duplexes.
• MM_PBSA method was utilized to estimate binding free energies.

Main Results:

• Watson-Crick hydrogen bonding remained intact in modified duplexes.
• Structural alterations, including changes in inter-base pair parameters and backbone torsional angles, were localized to the isonucleoside insertion site.
• Modified duplexes exhibited decreased stacking abilities and minor thermal destabilization compared to native DNA.
• Binding free energies of isonucleoside-containing duplexes were lower than native DNA duplexes.

Conclusions:

• Isonucleoside incorporation into DNA duplexes causes localized structural perturbations.
• These modifications lead to reduced thermal stability and lower binding free energies, consistent with experimental findings.
• The study provides structural insights into the behavior of isonucleoside-modified DNA.