Principles for computational design of binding antibodies


Natural proteins must both fold into a stable conformation and exert their molecular function. To date, computational design has successfully produced stable and atomically accurate proteins by using so-called “ideal” folds rich in regular secondary structures and almost devoid of loops and destabilizing elements, such as cavities. Molecular function, such as binding and catalysis, however, often demands nonideal features, including large and irregular loops and buried polar interaction networks, which have remained challenging for fold design. Through five design/experiment cycles, we learned principles for designing stable and functional antibody variable fragments (Fvs). Specifically, we (i) used sequence-design constraints derived from antibody multiple-sequence alignments, and (ii) during backbone design, maintained stabilizing interactions observed in natural antibodies between the framework and loops of complementarity-determining regions (CDRs) 1 and 2. Designed Fvs bound their ligands with midnanomolar affinities and were as stable as natural antibodies, despite having >30 mutations from mammalian antibody germlines. Furthermore, crystallographic analysis demonstrated atomic accuracy throughout the framework and in four of six CDRs in one design and atomic accuracy in the entire Fv in another. The principles we learned are general, and can be implemented to design other nonideal folds, generating stable, specific, and precise antibodies and enzymes.

Submission Details


Submitter: Stephanie Contreras

Submission Date: June 22, 2020, 11:31 a.m.

Version: 1

Publication Details
Dror Baran, M. Gabriele Pszolla, Gideon D. Lapidoth, Christoffer Norn, Orly Dym, Tamar Unger, Shira Albeck, Michael D. Tyka, Sariel J. Fleishman,Proceedings of the National Academy of Sciences of the United States of America (2017) Principles for computational design of binding antibodies
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
198.0 H,I design of antibodies P01857 IGHG1_HUMAN
190.2 H,I design of antibodies P01860 IGHG3_HUMAN
200.0 L,M design of antibodies P01834 IGKC_HUMAN
184.2 H,I design of antibodies P01861 IGHG4_HUMAN