A new strategy for designing a short-chain peptide ligand with high affinity to the Fc region of an antibody was proposed. The targeted antibody is human prostate specific antibody (PSA) derived from Mouse IgG2a. The ligand design strategy involves two major parts: binding site selection and peptide ligand design. One of the exposed hydrophobic patches near the bottom of the antibody's Fc region, identified from the molecular docking of naphthelene and end-capped tryptophan, was selected as the binding site. After examining the charge distribution around the binding site, various peptide ligands were designed according to the possible hydrophobic and electrostatic interactions. A peptide ligand, RRGW, was found to have high Fc binding affinity by the analysis of molecular dynamics (MD) simulation. The first two residues, two arginines, play an important role in electrostatic interaction between the peptide and the Fc region of the antibody. The fourth residue, the tryptophan, provides the VDW force; and the flexibility of peptide is achieved through the help of the third residue, the glycine. The binding affinity, recognition efficiency, and orientation factor were calculated from the results of surface plasmon resonance (SPR) measurements. The result shows that the dissociation constant is 5.56 × 10(-10) M(-1). We also found that the recognition efficiency and orientation factor on the ligand attached surface were much higher than those on negatively and positively charged surfaces. This approach provides a simple and fast strategy for small ligands design on oriented antibody immobilization.