Despite the high specificity between antigen and antibody binding, similar epitopes can be recognized or cross-neutralized by paratopes of antibody with different binding affinities. How to accurately characterize this slight variation which may or may not change the antigen-antibody binding affinity is a key issue in this area. In this report, by combining cylinder model with shell structure model, a new fingerprint was introduced to describe both the structural and physical-chemical features of the antigen and antibody protein. Furthermore, beside the description of individual protein, the specific epitope-paratope interaction fingerprint (EPIF) was developed to reflect the bond and the environment of the antigen-antibody interface. Finally, Proteochemometric Modeling of the antigen-antibody interaction was established and evaluated on 429 antigen-antibody complexes. By using only protein descriptors, our model achieved the best performance (R-2 = 0: 91; Q(test)(2) = 0: 68) among peers. Further, together with EPIF as a new cross-term, our model (R-2 = 0: 92; Q(2) test = 0: 74) can significantly outperform peers with multiplication of ligand and protein descriptors as a cross-term (R2