Identification of Structurally Related Antibodies in Antibody Sequence Databases Using Rosetta-Derived Position-Specific Scoring

The amount of antibody (Ab) variable gene sequence information is expanding rapidly, but our ability to predict the function of Abs from sequence alone is limited. Here, we describe a sequence-to-function prediction method that couples structural data for a single Ab/antigen (Ag) complex with repertoire data. We used a position-specific structure-scoring matrix (P3SM) incorporating structure-prediction scores from Rosetta to identify Ab variable loops that have predicted structural similarity to the influenza virus-specific human Ab CH65. The P3SM approach identified new members of this Ab class. Recombinant Ab expression, crystallography, and virus inhibition assays showed that the HCDR3 loops of the newly identified Abs possessed similar structure and antiviral activity as the comparator CH65. This approach enables discovery of new human Abs with desired structure and function using cDNA repertoires that are obtained readily with current amplicon sequencing techniques. •New position-specific structure-scoring matrix method using Rosetta•Effective sequence-to-function prediction for identifying virus-specific antibodies•Crystallography and virus inhibition assays validated the models Finn et al. describe a sequence-to-function prediction method that couples structural data for a single antibody-antigen complex with large-scale antibody variable gene repertoire data. Using a position-specific structure-scoring matrix incorporating structure-prediction scores from Rosetta, they identified Ab variable loops that have predicted structural similarity to an influenza virus-specific human antibody.