: In several previous studies, we performed sensitivity analysis to gauge the relative importance of different atomic partial charges in determining protein–ligand binding. In this work, we gain further insights by decomposing these results into three contributions: desolvation, intramolecular interactions, and intermolecular interactions, again based on a Poisson continuum electrostatics model. Three protein kinase–inhibitor systems have been analyzed: CDK2– deschloroflavopiridol, PKA–PKI, and LCK–PP2. Although our results point out the importance of specific intermolecular interactions to the binding affinity, they also reveal the remarkable contributions from the solventmediated intramolecular interactions in some cases. Thus, it is necessary to look beyond analyzing protein–ligand interactions to understand protein–ligand recognition or to gain insights into designing ligands and proteins. In analyzing the contributions of the three components to the overall binding free energy, the PKA–PKI system with a much larger ligand was found to behave differently from the other two systems with smaller ligands. In the former case, the intermolecular interactions are very favorable, and together with the favorable solvent-mediated intramolecular interactions, they overcome the large desolvation penalties to give a favorable electrostatics contribution to the overall binding affinity. On the other hand, the other two systems with smaller ligands only present modest intermolecular interactions and they are not or are only barely sufficient to overcome the desolvation penalty even with the aid of the favorable intramolecular contributions. As a result, the binding affinity of these two systems do not or only barely benefit from electrostatics contributions