ABSTRACT 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 ligandĘCreceptor recognition remains
to be elucidated. In this study, the structures
of NRG-1/ErbB3 and NRG-1/ErbB4 complexes were
modeled based on the available structures of the
homologous proteins. The binding free energies of
NRG-1 to ErbB3 and ErbB4 were calculated using
the molecular mechanics PoissonĘCBoltzmann surface
area (MM-PBSA) computational method. In
addition, computational alanine-scanning mutagenesis
was performed in the binding site of NRG-1
and the difference in the binding free energies
between NRG-1 mutants and the receptors was
calculated. The results specify the contribution of
each residue at the interaction interfaces to the
binding affinity of NRG-1 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-1/ErbB3 and
NRG-1/ErbB4 complexes are reliable and could be
used to guide future studies, such as performing
desirable mutations on NRG-1 to increase the binding
affinity and selectivity to the receptor and discovering
new therapeutic agents for the treatment of
heart failure. Proteins 2005;59:742ĘC756.