Many ligands simultaneously interact with multiple protein chains in quaternary structure (QS). However, a significant number of previous studies on template-based modeling of protein-ligand interactions were based on monomeric structure (MS), which may suffer from incomplete binding information. The defects of using MS rather than QS have not been systematically studied before. In this work, based on molecular docking experiments and binding free energy estimations, we performed a large-scale comparison of the protein-ligand interactions in both forms of structures. We found that 1) about 18.6 percent biologically relevant ligands bind multiple chains in QS simultaneously. 2) For more than 95 percent complexes with multiple chains involved in the interactions, the binding free energy is lower for the QS form than the MS form. 3) For over 70 percent complexes with multi-chain binding pockets, docking with QS yields more accurate ligand conformations than with MS. While for about 1.82 percent complexes, accurate docking conformations were obtained by MS. Based on this work, it is encouraged to make use of QS rather than MS in future studies on protein-ligand interactions.