Assessing the performance of MM/PBSA and MM/GBSA methods. 10. Prediction reliability of binding affinities and binding poses for RNA-ligand complexes.

Ribonucleic acid (RNA)-ligand interactions play a pivotal role in a wide spectrum of biological processes, ranging from protein biosynthesis to cellular reproduction. This recognition has prompted the broader acceptance of RNA as a viable candidate for drug targets. Delving into the atomic-scale understanding of RNA-ligand interactions holds paramount importance in unraveling intricate molecular mechanisms and further contributing to RNA-based drug discovery. Computational approaches, particularly molecular docking, offer an efficient way of predicting the interactions between RNA and small molecules. However, the accuracy and reliability of these predictions heavily depend on the performance of scoring functions (SFs). In contrast to the majority of SFs used in RNA-ligand docking, the end-point binding free energy calculation methods, such as molecular mechanics/generalized Born surface area (MM/GBSA) and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA), stand as theoretically more rigorous approaches. Yet, the evaluation of their effectiveness in predicting both binding affinities and binding poses within RNA-ligand systems remains unexplored. This study first reported the performance of MM/PBSA and MM/GBSA with diverse solvation models, interior dielectric constants () and force fields in the context of binding affinity prediction for 29 RNA-ligand complexes. MM/GBSA is based on short (5 ns) molecular dynamics (MD) simulations in an explicit solvent with the YIL force field; the GB model with higher interior dielectric constant ( = 12, 16 or 20) yields the best correlation ( = -0.513), which outperforms the best correlation ( = -0.317, rDock) offered by various docking programs. Then, the efficacy of MM/GBSA in identifying the near-native binding poses from the decoys was assessed based on 56 RNA-ligand complexes. However, it is evident that MM/GBSA has limitations in accurately predicting binding poses for RNA-ligand systems, particularly compared with notably proficient docking programs like rDock and PLANTS. The best top-1 success rate achieved by MM/GBSA rescoring is 39.3%, which falls below the best results given by docking programs (50%, PLNATS). This study represents the first evaluation of MM/PBSA and MM/GBSA for RNA-ligand systems and is expected to provide valuable insights into their successful application to RNA targets.