A computer model of the beta-chain of C4b-binding protein (C4BP) was constructed, using the backbone fold of the NMR structures of the sixteenth CP module of factor H (H16) and of a pair of modules consisting of the fifteenth and sixteenth CPs of factor H (H15-16). The characteristic hydrophobic core responsible for dictating the three-dimensional structure of the CP family is conserved in the amino acid sequence of C4BP beta 1, beta 2 and beta 3. The distribution of the electrostatic potential shows that the model is mainly covered by a negative contour. Interestingly, a positive area is observed in the C-terminal region of the first CP module, enclosing peptide 31-45, known to be a binding site for protein S. This observation suggests that electrostatic interactions can be of importance for the interaction of C4BP to protein S. A solvent-accessible hydrophobic patch, located nearby and involving the peptide 31-45, was also found in the model, further confirming that this area is involved in the interaction with protein S. The contribution of beta-chain residues 31-45 to the affinity for protein S was studied further by means of synthetic mutant peptides. The results suggest that both electrostatic and hydrophobic interactions are important for the binding to protein S.