Accurate modeling of cation-π interactions in enzymes: a case study on the CDPCho:phosphocholine cytidylyltransferase complex

Cation-pi interactions are functionally relevant, strong secondary interactions that play versatile roles in a variety of chemical and biological systems. Therefore, it is very important to be able to describe accurately and reliably these interactions. In this study, we propose a methodology for the accurate modeling of cation-pi interactions in proteins using QM/MM calculations. We developed a methodology for computing the many-body interaction energy terms and tested the effect of various factors on the accuracy of the binding energy. We found that once well-equilibrated structures were reached in the MD simulations, very similar results can be obtained for the various snapshots taken from the trajectory. The calculated interaction energies were only slightly influenced by electrostatic embedding of the point charges in the QM/MM calculations and by QM/MM geometry optimization. The calculated molecular mechanics interaction energies were off by 50 % for cation-pi interactions. Instead, we suggest the calibration of force fields based on fragment-based QM calculations on geometries obtained from MD simulations to yield reliable binding energies at reduced computational cost.