Ensemble molecular dynamics for predicting binding energies of DNA intercalators

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Drug Discovery

Background:

• Ensemble molecular dynamics (MD) simulations enhance protein-ligand binding energy predictions.
• Application of ensemble MD to DNA-ligand systems is less explored.
• Previous studies focused on specific DNA-intercalator complexes like doxorubicin and proflavine.

Purpose of the Study:

• To extend ensemble MD simulations for predicting binding energies of diverse DNA-intercalator complexes.
• To evaluate the accuracy and efficiency of the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method with corrections.
• To determine the optimal number of MD replicas for reliable binding affinity predictions.

Main Methods:

• Simulated 25 independent 10 ns MD replicas for 16 DNA-intercalator complexes.
• Applied uncorrected and corrected MM/PBSA methods to calculate binding energies.
• Utilized bootstrap analyses to assess the convergence and uncertainty of predictions.
• Validated the method with two additional monocationic intercalators.

Main Results:

• Uncorrected MM/PBSA energies showed poor correlation (R²=0.45) with experimental values.
• MM/PBSA energies corrected for entropy and deformation improved predictions for cationic intercalators (R²=0.70, within 2 kcal mol⁻¹).
• Bootstrap analysis indicated 10-20 independent replicas are generally sufficient for reliable predictions.

Conclusions:

• Corrected MM/PBSA energies from ensemble MD simulations are reliable and efficient for predicting DNA-intercalator binding affinity.
• This computational approach offers a valuable alternative to costly or impractical experimental binding measurements.
• The findings support the use of ensemble MD simulations for drug design and development involving DNA-targeting agents.