Explicit Representation of Cation−π Interactions in Force Fields with 1/r4 Nonbonded Terms

The binding energies for cation−π complexation are underestimated by traditional fixed-charge force fields owing to their lack of explicit treatment of ion-induced dipole interactions. To address this deficiency, an explicit treatment of cation−π interactions has been introduced into the OPLS-AA force field. Following prior work with atomic cations, it is found that cation−π interactions can be handled efficiently by augmenting the usual 12–6 Lennard-Jones potentials with 1/r4 terms. Results are provided for prototypical complexes as well as protein–ligand systems of relevance for drug design. Alkali cation, ammonium, guanidinium, and tetramethylammonium were chosen for the representative cations, while benzene and six heteroaromatic molecules were used as the π systems. The required nonbonded parameters were fit to reproduce structure and interaction energies for gas-phase complexes from density functional theory (DFT) calculations at the ωB97X-D/6-311++G(d,p) level. The impact of the solvent was then examined by computing potentials of mean force (pmfs) in both aqueous and tetrahydrofuran (THF) solutions using the free-energy perturbation (FEP) theory. Further testing was carried out for two cases of strong and one case of weak cation−π interactions between druglike molecules and their protein hosts, namely, the JH2 domain of JAK2 kinase and macrophage migration inhibitory factor. FEP results reveal greater binding by 1.5–4.4 kcal/mol from the addition of the explicit cation−π contributions. Thus, in the absence of such treatment of cation−π interactions, errors for computed binding or inhibition constants of 101–103 are expected.