Searching for a Reliable Density Functional for Molecule–Environment Interactions, Found B97M-V/def2-mTZVP

In the present study, we have examined density functional theory methods for the calculation of the interaction energy between a small molecule and its environment. For simple systems such as a neutral solute in a neutral solvent, good accuracy can be attained using low-cost “3c” methods, in particular r2SCAN-3c. When part(s) of the system is charged, the accurate computation of the interactions is more challenging. In these cases, we find the B97M-V/def2-mTZVP method to agree well with reference values; it also shows good accuracy for the more straightforward neutral systems. Thus, B97M-V/def2-mTZVP provides a means for accurate and low-cost computation of interaction energies, notably the binding between a substrate or a drug molecule and an enzyme, which may facilitate rational drug design.