title: AbDesign: An algorithm for combinatorial backbone design guided by natural conformations and sequences.
abstract: Computational design of protein function has made substantial progress, generating new enzymes, binders, inhibitors, and nanomaterials not previously seen in nature. However, the ability to design new protein backbones for function--essential to exert control over all polypeptide degrees of freedom--remains a critical challenge. Most previous attempts to design new backbones computed the mainchain from scratch. Here, instead, we describe a combinatorial backbone and sequence optimization algorithm called AbDesign, which leverages the large number of sequences and experimentally determined molecular structures of antibodies to construct new antibody models, dock them against target surfaces and optimize their sequence and backbone conformation for high stability and binding affinity. We used the algorithm to produce antibody designs that target the same molecular surfaces as nine natural, high-affinity antibodies; in five cases interface sequence identity is above 30%, and in four of those the backbone conformation at the core of the antibody binding surface is within 1 Å root-mean square deviation from the natural antibodies. Designs recapitulate polar interaction networks observed in natural complexes, and amino acid sidechain rigidity at the designed binding surface, which is likely important for affinity and specificity, is high compared to previous design studies. In designed anti-lysozyme antibodies, complementarity-determining regions (CDRs) at the periphery of the interface, such as L1 and H2, show greater backbone conformation diversity than the CDRs at the core of the interface, and increase the binding surface area compared to the natural antibody, potentially enhancing affinity and specificity.
authors: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors: Gideon D
authors: GD
authors: Lapidoth
authors: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors: Dror
authors: D
authors: Baran
authors: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors: Gabriele M
authors: GM
authors: Pszolla
authors: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors: Christoffer
authors: C
authors: Norn
authors: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors: Assaf
authors: A
authors: Alon
authors: Google Inc., 1600 Amphitheatre Pkwy, Mountain View, California, 94043.
authors: Michael D
authors: MD
authors: Tyka
authors: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors: Sarel J
authors: SJ
authors: Fleishman
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D022801:Complementarity Determining Regions / Q000737:chemistry*; D019295:Computational Biology / Q000379:methods*; D017143:Fuzzy Logic; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D015202:Protein Engineering / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*
chemical_list: D022801:Complementarity Determining Regions
keywords: CDRs; Rosetta; V(D)J recombination; canonical conformations; computational protein design; conformation-sequence optimization; fuzzy-logic design; modular segments