Making density functional theory accurate for non-covalent interactions involving ionic system

Density Functional Theory (DFT) often falls short in accurately capturing non-covalent interactions (NCIs) in a range of complex molecular environments, particularly those found in enzyme systems where ionic species play a central role. The limitations of standard DFT methods lead to inaccuracies in modeling these biologically relevant systems, affecting predictions of binding affinities and conformational stability. Here, we address this challenge by applying the principles of transferability [Chem. Sci, 15(28), 11122] to improve dispersion corrections within DFT frameworks. Our approach demonstrates significantly enhanced reliability in describing NCIs across various enzyme classes, particularly in charged active sites. We also rigorously evaluated the performance of our method on the prediction of interaction energy of neutral complexes and conformational changes of drug-like molecules, which indicate the balanced description of our methods on both ionic and neutral systems. These results highlight the potential of refined dispersion models to resolve long-standing issues in DFT for biochemically relevant ionic interactions, offering new avenues for accurately modeling enzymatic processes.