Thermodynamic Parameter Estimation for Modified Oligonucleotides Using Molecular Dynamics Simulations

This study investigates the thermodynamic parameters of 1300 RNA/DNA hybrid duplexes, including both natural and chemically modified forms, using molecular dynamics (MD) simulations. Modified duplexes consist of phosphorothioate (PS) backbones and 2'-<i>O</i>-methoxyethyl (MOE) modifications, both commonly used in therapeutic oligonucleotides. Hybridization enthalpy and entropy were calculated from MD trajectories using molecular mechanics Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics generalized Born surface area (MMGBSA) approaches. To address discrepancies with experimental data, we established empirical relationships by comparing calculated values with known experimental results of natural hybrid duplexes, then extended these relationships to the entire data set. The corrected parameters were subsequently used to generate nearest-neighbor (NN) models, allowing for experimentally reliable melting temperature predictions. In this process, MMGBSA demonstrated superior predictive performance with high convergence and consistency for both natural and modified duplexes. Specifically, MMGBSA captured the stabilizing effects of the MOE modification with minimal bias, while MMPBSA exhibited greater variability and limited reliability. These findings highlight the potential of MMGBSA for accurate thermodynamic modeling of both natural and modified nucleic acids, providing a robust framework and experimentally meaningful insights for applications in nucleic acid-based therapeutic design and biotechnology.