Abstract: Prediction of a preferred position and orientation of a ligand bound to a macromolecule is described. The ligand and the macromolecule can form a stable complex based on matching of physico-chemical properties and probabilistic relaxation labeling. The macromolecule can be a protein and a physico-chemical property can be hydrogen bonding. A potential docking location for the ligand on the surface of the protein is determined. Then, on the potential docking location and the ligand, the donor and acceptor atoms are identified. Probabilistic relaxation labeling is utilized to facilitate identification of the potential matching pairs of donors and acceptors, according to local shape complementarity and a geometric constraint for the conformation of hydrogen bond. A scoring function can rank the potential matching pairs to obtain the preferred ligand position.