Significance: Natural antibodies perform their biological function by recognizing all sorts of foreign proteins—seemly unlimited structural and sequence diversities in antigens can be recognized by a limited repertoire of antibodies, for which the sequence and structure are relatively homogeneous. We found that the energetically critical epitope portions are largely composed of backbone atoms, side-chain carbons, and hydrogen bond donors/acceptors. These key components are ubiquitous on protein surfaces and can be recognized by the enriched aromatic side chains and, to a lesser extent, short-chain hydrophilic residues on the antibody paratopes; antibodies, with relatively limited sequence and structural diversities in the antigen binding sites, can recognize unlimited protein antigens through recognizing the common physicochemical features on all protein surfaces.