The solubility of globular proteins is a basic biophysical property that is usually a prerequisite for their functioning. In this study, we probed the solubility of globular proteins with the help of the statistical potential formalism, in view of objectifying the connection of solubility with structural and energetic properties and of the solubility-dependence of specific amino acid interactions. We started by setting up two independent datasets containing either soluble or aggregation-prone proteins with known structures. From these two datasets, we computed solubility-dependent distance potentials that are by construction biased towards the solubility of the proteins from which they are derived. Their analysis showed the clear preference of amino acid interactions such as Lys-containing salt bridges and aliphatic interactions to promote protein solubility, whereas others such as aromatic, His-π, cation-π, amino-π and anion-π interactions rather tend to reduce it. These results indicate that interactions involving delocalized π-electrons favor aggregation, unlike those involving no (or few) dispersion forces. Furthermore, using our potentials derived from either highly or weakly soluble proteins to compute protein folding free energies, we found that the difference between these two energies correlates better with solubility than other properties analyzed before such as protein length, isoelectric point and aliphatic index. This is, to the best of our knowledge, the first comprehensive in silico study of the impact of residue-residue interactions on protein solubility properties.The results of this analysis provide new insights that will facilitate future rational protein design applications aimed at modulating the solubility of targeted proteins.