Taking hydrogen bonds as a basis to explore biomolecular properties and interactions, we constructed the lone-pair electron (LPE) index and a molecular orbital fingerprint based on molecular hybrid orbitals to represent the ability of molecules to form hydrogen bonds. Then, a computational model was constructed to predict molecular interactions. The LPE and orbital fingerprint could effectively predict the biological properties and bioactivities of molecules. This study revealed the significance of hybrid orbitals for understanding cell biochemistry.