Do the complexity and the bulkiness of a protein affect the affinity between protein and ligand? We attempted to investigate this problem by using ab initio fragment molecular orbital (FMO) method to calculate the binding energy between human influenza viral hemagglutinin (HA) and human oligo-saccharide receptor. We compared the binding energies of 4 different sizes of human A virus HA H3 subtype complexed with human receptor Neu5Ac(alpha 2-6)Gal as a model. The full shape receptor binding domain complexed with Neu5Ac(alpha 2-6)Gal had the highest binding energy 170.3 kcal/mol at the FMO-HF/STO-3G level, which was 52.3 kcal/mol higher than that of the smallest domain-receptor complex. These data provide the consideration of the backyard bulkiness beyond the binding site of protein to the protein-ligand stability. (c) 2006 Elsevier Inc. All rights reserved.