Antibodies are key therapeutic biomolecules yet the principles underlying diverse paratopes binding to the same epitope remain unexplained. An insufficient understanding of the structural rules of antibody-antigen binding, due to a lack of experimentally resolved structures, leads to the current inability to characterize antibody variants in silico. Here we explore a rule-based antibody design strategy that relies on a thorough understanding of epitope-paratope interactions, in contrast to generative design based on millions of trials and errors. We identified the epitope of five affinity-verified complexes between HER2 and Trastuzumab variants using cryo-EM and position-resolved HDX-MS. Computational analysis of modeled structural conformational ensembles replicate and expand experimental results and highlight the importance of flexibility in understanding high and low-affinity binders. Structural parameters calculated based on geometry, surface, and biochemical properties were able to stratify antibodies by affinity. Overall, our study describes the binding rules of the paratope variants, showing how antibodies with diverse sequences share similar structural binding rules.