Calculation of binding free energy of short double stranded oligonucleotides using MM/3D-RISM-KH approach

Abstract

We calculated the binding free energy of short oligonucleotides (9–20-mers DNA) by using molecular dynamics, followed with post-processing based on molecular theory of solvation (MM/3D-RISM-KH approach). A comparison with the PBSA and GBSA continuum solvation models was performed to identify the approach in the best agreement with experimental results for the binding free energy. Compared to the PBSA or GBSA methods, the 3D-RISM-KH molecular theory of solvation provides a more accurate description of the nonpolar contribution to the solvation free energy from the first principles of statistical mechanics. The binding free energy was calculated by using separate trajectories for the DNA complex and its two strands, as well as based on a single trajectory for the complex, both with and without account for explicit counter ions in post-processing of molecular dynamics trajectories to calculate the binding free energy of oligonucleotides. Overall, both GBSA and 3D-RISM-KH predict the binding free energy obtained from “separate trajectory” calculations with implicit account for counter ions in a good agreement with experiment, the latter showing a better performance for larger oligonucleotides.