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Structural prediction of antibody‐APRIL complexes by computational docking constrained by antigen saturation mutagenesis library data
Author(s) -
Wollacott Andrew M.,
Robinson Luke N.,
Ramakrishnan Boopathy,
Tissire Hamid,
Viswanathan Karthik,
Shriver Zachary,
Babcock Gregory J.
Publication year - 2019
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.2778
Subject(s) - antibody , docking (animal) , saturated mutagenesis , computational biology , antigen , epitope , mutagenesis , biology , rational design , computational model , protein engineering , chemistry , immunology , computer science , biochemistry , genetics , mutation , gene , medicine , simulation , enzyme , nursing , mutant
IgA nephropathy (IgAN) is the most prevalent cause of primary glomerular disease worldwide, and the cytokine A PRoliferation‐Inducing Ligand (APRIL) is emerging as a key player in IgAN pathogenesis and disease progression. For a panel of anti‐human APRIL antibodies with known antagonistic activity, we sought to define their structural mode of engagement to understand molecular mechanisms of action and aid rational antibody engineering. Reliable computational prediction of antibody‐antigen complexes remains challenging, and experimental methods such as X‐ray co‐crystallography and cryoEM have considerable technical, resource, and throughput barriers. To overcome these limitations, we implemented an integrated and accessible experimental‐computational workflow to more accurately predict structures of antibody‐APRIL complexes. Specifically, a yeast surface display library encoding site‐saturation mutagenized surface positions of APRIL was screened against a panel of anti‐APRIL antibodies to rapidly obtain a comprehensive biochemical profile of mutational impact on binding for each antibody. The experimentally derived mutational profile data were used as quantitative constraints in a computational docking workflow optimized for antibodies, resulting in robust structural models of antibody‐antigen complexes. The model results were confirmed by solving the cocrystal structure of one antibody‐APRIL complex, which revealed strong agreement with our model. The models were used to rationally select and engineer one antibody for cross‐species APRIL binding, which quite often aids further testing in relevant animal models. Collectively, we demonstrate a rapid, integrated computational‐experimental approach to robustly predict antibody‐antigen structures information, which can aid rational antibody engineering and provide insights into molecular mechanisms of action.