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|Title:||Rapid Structural Characterization of Human Antibody-Antigen Complexes through Experimentally Validated Computational Docking|
|Authors:||SIMONELLI L.; BELTRAMELLO Martina; YUDINA Zinaida; MACAGNO Annalisa; CALZOLAI LUIGI; VARANI Luca|
|Citation:||JOURNAL OF MOLECULAR BIOLOGY vol. 396 no. 5 p. 1491-1507|
|Publisher:||ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD|
|Type:||Articles in periodicals and books|
|Abstract:||If we understand the structural rules governing antibody (Ab)-antigen (Ag) interactions in a given virus, then we have the molecular basis to attempt to design and synthesize new epitopes to be used as vaccines or optimize the antibodies themselves for passive immunization. Comparing the binding of several different antibodies to related Ags should also further our understanding of general principles of recognition. To obtain and compare the three-dimensional structure of a large number of different complexes, however, we need a faster method than traditional experimental techniques. While biocomputational docking is fast, its results might not be accurate. Combining experimental validation with computational prediction may be a solution. As a proof of concept, here we isolated a monoclonal Ab from the blood of a human donor recovered from dengue virus infection, characterized its immunological properties, and identified its epitope on domain III of dengue virus E protein through simple and rapid NMR chemical shift mapping experiments. We then obtained the three-dimensional structure of the Ab/Ag complex by computational docking, using the NMR data to drive and validate the results. In an attempt to represent the multiple conformations available to flexible Ab loops, we docked several different starting models and present the result as an ensemble of models equally agreeing with the experimental data. The Ab was shown to bind a region accessible only in part on the viral surface, explaining why it cannot effectively neutralize the virus.|
|JRC Directorate:||Institute for Health and Consumer Protection Historical Collection|
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