The nature and strength of the cation-π interaction in protein-ligand binding are modeled by considering a series of nonbonded complexes involving N-substituted piperidines and substituted monocylic aromatics that mimic the δ-opioid receptor-ligand binding. High-level ab initio quantum mechanical calculations confirm the importance of such cation-π interactions, whose intermolecular interaction energy ranges from -6 to -12 kcal/mol. A better understanding of the electrostatics, polarization, and other intermolecular interactions is obtained by appropriately decomposing the total interaction energy into their individual components. The energy decomposition analysis is also useful for parametrizing existing molecular mechanics force fields that could then account for energetic contributions arising out of cation-π interactions in biomolecules. The present results further provide a framework for interpreting experimental results from point mutation reported for the δ-opioid receptor.