We describe a model that relates the optimal size of a globular protein domain to the ratio between hydrophilic and hydrophobic amino acid residues. This model represents a domain as a homogeneous spherical assembly of monodisperse spheres corresponding to the individual residues; the hydrophilic spheres are distributed on the assembly surface, and the hydrophobic spheres are buried in the core. The model predicts that a domain with a 1: 1 ratio of hydrophilic and hydrophobic residues is composed of 156 residues. It also predicts that smaller protein domains have more hydrophilic, than hydrophobic residues. These predictions are in agreement with the distribution of domain size and residue composition for the experimentally determined protein structures. (c) 2005 Elsevier B.V. All rights reserved.