Abstract
In recent years, the observed antibody sequence space has grown exponentially due to advances in high-throughput sequencing of immune receptors. The rise in sequences has not been mirrored by a rise in structures, as experimental structure determination techniques have remained low-throughput. Computational modeling, however, has the potential to close the sequence-structure gap. To achieve this goal, computational methods must be robust, fast, easy to use, and accurate. Here we report on the latest advances made in RosettaAntibody and Rosetta SnugDock-methods for antibody structure prediction and antibody-antigen docking. We simplified the user interface, expanded and automated the template database, generalized the kinematics of antibody-antigen docking (which enabled modeling of single-domain antibodies) and incorporated new loop modeling techniques. To evaluate the effects of our updates on modeling accuracy, we developed rigorous tests under a new scientific benchmarking framework within Rosetta. Benchmarking revealed that more structurally similar templates could be identified in the updated database and that SnugDock broadened its applicability without losing accuracy. However, there are further advances to be made, including increasing the accuracy and speed of CDR-H3 loop modeling, before computational approaches can accurately model any antibody.
Highlights
Antibodies are a crucial component of the adaptive immune system of vertebrates
While grafting is a fast process ( 10 mins per model), complementarity determining region (CDR)-H3 loop modeling is time consuming, so the tests were split based on their runtime
We investigated the structural similarity between the fragment sets picked for loop modeling and the corresponding target antibody CDR-H3 loop or other protein loop
Summary
Antibodies are a crucial component of the adaptive immune system of vertebrates. They are antigen-specific and can be directed towards virtually any antigen to protect us from infections. Their high specificity, in combination with their favorable biophysical properties and pharmacodynamics, have allowed for their development and use as drugs, diagnostics, and research reagents. The isotype is determined by the constant region that dictates effector functions and half life. These constant regions are the same for antibodies of the same isotype. The variable fragments (Fv) on the other hand, are unique to each monoclonal antibody and provide antigen specificity
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