The neuregulin/ErbB system is a growth factor/receptor cascade that has been proven to be essential in the development of the heart and the sympathetic nervous system. However, the basis of the specificity of ligand–receptor recognition remains to be elucidated. In this study, the structures of NRG-1β/ErbB3 and NRG-1β/ErbB4 complexes were modeled based on the available structures of the homologous proteins. The binding free energies of NRG-1β to ErbB3 and ErbB4 were calculated using the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) computational method. In addition, computational alanine-scanning mutagenesis was performed in the binding site of NRG-1β and the difference in the binding free energies between NRG-1β mutants and the receptors was calculated. The results specify the contribution of each residue at the interaction interfaces to the binding affinity of NRG-1β with ErbB3 and ErbB4, identifying several important interaction residue pairs that are in agreement with previously acquired experimental data. This indicates that the presented structural models of NRG-1β/ErbB3 and NRG-1β/ErbB4 complexes are reliable and could be used to guide future studies, such as performing desirable mutations on NRG-1β to increase the binding affinity and selectivity to the receptor and discovering new therapeutic agents for the treatment of heart failure. Proteins 2005. © 2005 Wiley-Liss, Inc.