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Computational antibody engineering efforts to date have focused on improving binding affinities or biophysical characteristics.  De novo  design of antibodies binding specific epitopes could greatly accelerate discovery of therapeutics as compared to conventional immunization or synthetic library selection strategies. Here, we employed  de novo  complementarity determining region (CDR) design to engineer targeted antibody–antigen interactions using previously described  in silico  methods. CDRs predicted to bind the minimal FLAG peptide (Asp–Tyr–Lys–Asp) were grafted onto a single-chain variable fragment (scFv) acceptor framework. Fifty scFvs comprised of designed heavy and light or just heavy chain CDRs were synthesized and screened for peptide binding by phage ELISA. Roughly half of the designs resulted in detectable scFv expression. Four antibodies, designed entirely  in silico , bound the minimal FLAG sequence with high specificity and sensitivity. When reformatted as soluble antigen-binding fragments (Fab), these clones expressed well, were predominantly monomeric and retained peptide specificity. In both formats, the antibodies bind the peptide only when present at the amino-terminus of a carrier protein and even conservative peptide amino acid substitutions resulted in a complete loss of binding. These results support  in silico  CDR design of antibody specificity as an emerging antibody engineering strategy.

De novo design of antibody complementarity determining regions binding a FLAG tetra-peptide