Comprehensive Evaluation of End-Point Free Energy Methods in DNA–Ligand Interaction Predictions

作者：Cuiyu Li, Hongyan Du, Chengwei Zhang, Wanying Huang, Xujun Zhang, Tianyue Wang, Dejun Jiang, Tingjun Hou, Ercheng Wang · 发表于：Journal of Chemical Information and Modeling · 年份：2025 · DOI：10.1021/acs.jcim.4c01947 · 被引用次数：5 · 研究领域：DNA and Nucleic Acid Chemistry、RNA and protein synthesis mechanisms、Protein Structure and Dynamics

Deoxyribonucleic acid (DNA) serves as a repository of genetic information in cells and is a critical molecular target for various antibiotics and anticancer drugs. A profound understanding of small molecule interaction with DNA is crucial for the rational design of DNA-targeted therapies. While the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) and molecular mechanics/generalized Born surface area (MM/GBSA) approaches have been well established for predicting protein–ligand binding, their application to DNA–ligand interactions has been less explored. In this study, we systematically investigated the binding of 13 diverse small molecules to DNA, evaluating the accuracy of DNA–ligand interaction predictions across different solvation approaches, interior dielectric constants (ε in ), and molecular force fields. Our results demonstrate that MM/PBSA, using energy-minimized structures (the bsc1 force field and ε in = 20), provides the best correlation ( R p = −0.742) with experimental binding affinities, surpassing the performance of rDock scoring functions (best R p = −0.481). Notably, the interior dielectric constant was found to significantly impact DNA–ligand binding free energy predictions, especially for MM/PBSA. Moreover, both MM/PBSA and MM/GBSA predictions (ε in = 16 or 20) exhibited superior performance in distinguishing native-like binding modes within the top-10 poses from decoys, compared to the molecular docking tools used in this study. However, the po...