Machine Learning Meets Physics-based Modeling: A Mass-spring System to Predict Protein-ligand Binding Affinity

Computational assessment of the energetics of protein-ligand complexes is a challenge in the early stages of drug discovery. Previous comparative studies on computational methods to calculate the binding affinity showed that targeted scoring functions outperform universal models.

The goal here is to review the application of a simple physics-based model to estimate the binding. The focus is on a mass-spring system developed to predict binding affinity against cyclin-dependent kinase.

Publications in PubMed were searched to find mass-spring models to predict binding affinity. Crystal structures of cyclin-dependent kinases found in the protein data bank and two web servers to calculate affinity based on the atomic coordinates were employed.

One recent study showed how a simple physics-based scoring function (named Taba) could contribute to the analysis of protein-ligand interactions. Taba methodology outperforms robust physics-based models implemented in docking programs such as AutoDock4 and Molegro Virtual Docker. Predictive metrics of 27 scoring functions and energy terms highlight the superior performance of the Taba scoring function for cyclin- dependent kinase.

The recent progress of machine learning methods and the availability of these techniques through free libraries boosted the development of more accurate models to address protein-ligand interactions. Combining a naïve mass-spring system with machine-learning techniques generated a targeted scoring function with superior predictive performance to estimate pK_i.