Accurate prediction of DNA-Intercalator binding energies: Ensemble of short or long molecular dynamics simulations?
Year: 2025
Type: article
Abstract: Despite the wide use of molecular dynamics (MD) simulations for binding energy predictions in biomolecular systems, results from single MD simulations are non-reproducible and often deviate from experimental values, even when longer simulations are used. This study addresses these limitations using ensemble MD simulations for the formation of DNA-intercalator complexes. Twenty-five replicas of short (10 ns) and long (100 ns) MD simulations were performed on different intercalators binding into DNA. The MM/PBSA and MM/GBSA binding energies of the Doxorubicin intercalating into DNA, including entropy and deformation energy corrections, are -7.3 ± 2.0 kcal/mol and -8.9 ± 1.6 kcal/mol, using 25 replicas of 100 ns. These values were closely reproduced even with shorter simulations of 10 ns, where the energies, averaged over 25 replicas, are -7.6 ± 2.4 kcal/mol (MM/PBSA) and -8.3 ± 2.9 kcal/mol (MM/GBSA). In both cases, the energies align well with the experimental range of -7.7 ± 0.3 to -9.9 ± 0.1 kcal/mol. This shows that reproducibility and accuracy of the binding energies depend more on the number of replicas than on the simulation length. The study was repeated for the DNA-Proflavine system, where the corrected MM/PBSA and MM/GBSA binding energies, averaged over 25 replicas of 10 ns each, are -5.6 ± 1.4 and -5.3 ± 2.3 kcal/mol, respectively. These are congruent with the experimental range of -5.9 to -7.1 kcal/mol. Bootstrap analyses revealed that 6 replicas of 100 ns or 8 replicas of 10 ns provide a good balance between computational efficiency and accuracy within 1.0 kcal/mol from experimental values.
Institution: United Arab Emirates University
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Award: G233174666
OpenAlex ID: W4407856550