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Prediction of VH–VL domain orientation for antibody variable domain modeling
Author(s) -
Bujotzek Alexander,
Dunbar James,
Lipsmeier Florian,
Schäfer Wolfgang,
Antes Iris,
Deane Charlotte M.,
Georges Guy
Publication year - 2015
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24756
Subject(s) - antibody , homology modeling , orientation (vector space) , mathematics , computational biology , chemistry , biology , genetics , geometry , biochemistry , enzyme
The antigen‐binding site of antibodies forms at the interface of their two variable domains, VH and VL, making VH–VL domain orientation a factor that codetermines antibody specificity and affinity. Preserving VH–VL domain orientation in the process of antibody engineering is important in order to retain the original antibody properties, and predicting the correct VH–VL orientation has also been recognized as an important factor in antibody homology modeling. In this article, we present a fast sequence‐based predictor that predicts VH–VL domain orientation with Q 2 values ranging from 0.54 to 0.73 on the evaluation set. We describe VH–VL orientation in terms of the six absolute ABangle parameters that have recently been proposed as a means to separate the different degrees of freedom of VH–VL domain orientation. In order to assess the impact of adjusting VH–VL orientation according to our predictions, we use the set of antibody structures of the recently published Antibody Modeling Assessment (AMA) II study. In comparison to the original AMAII homology models, we find an improvement in the accuracy of VH–VL orientation modeling, which also translates into an improvement in the average root‐mean‐square deviation with regard to the crystal structures. Proteins 2015; 83:681–695. © 2015 Wiley Periodicals, Inc.