Modeling and docking of antibody structures with Rosetta

Abstract

We describe Rosetta-based computational protocols for predicting the three-dimensional structure of an antibody from sequence (RosettaAntibody) and then docking the antibody to protein antigens (SnugDock). Antibody modeling leverages canonical loop conformations to graft large segments from experimentally-determined structures as well as (1) energetic calculations to minimize loops, (2) docking methodology to refine the VL–VH relative orientation, and (3) de novo prediction of the elusive complementarity determining region (CDR) H3 loop. To alleviate model uncertainty, antibody–antigen docking resamples CDR loop conformations and can use multiple models to represent an ensemble of conformations for the antibody, the antigen or both. These protocols can be run fully-automated via the ROSIE web server (http://rosie.rosettacommons.org/) or manually on a computer with user control of individual steps. For best results, the protocol requires roughly 1,000 CPU-hours for antibody modeling and 250 CPU-hours for antibody–antigen docking. Tasks can be completed in under a day by using public supercomputers.

Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility

“…Nevertheless, encouraging results are emerging for computational design methods to optimize antibody affinity, stability and/or solubility [56, 78–80]. Future efforts will also need to improve structural predictions of antibody CDRs [81, 82] – especially the long and highly variable heavy chain CDR3 – to accurately predict CDR mutations that are beneficial to different antibody properties. The continued development of such computational methods is expected to make experimental screening methods more efficient and enable the rapid generation of antibodies with optimized properties for diverse therapeutic applications.…”

Targeting HIV Env immunogens to B cell follicles in non-human primates through immune complex or protein nanoparticle formulations

“…A model of the Fv region of RM19R was generated using the Rosetta antibody protocol available on the ROSIE server 66,67 . An initial molecular model of the BG505 SOSIP trimer/RM19R Fab complexes was built by docking the Env portion of PDB: 5ACO 68 into the EM density maps along with the RM19R Fv model generated in Rosetta using UCSF Chimera 65 .…”

An epitope‐directed antibody affinity maturation system utilizing mammalian cell survival as readout

“…Next, we established structure models of the scFvs by combination of Rosetta (Weitzner et al, 2017) and MD calculations using GROMACS2016.3 (Abraham et al, 2015), which was followed by structural clustering (Supporting Information Figure S7). The representative structures of the top five clusters were almost the same most F I G U R E 3 Result of library screening.…”