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Int. J. Mol. Sci. 2011, 12, 226-251; doi:10.3390/ijms12010226

International Journal of

Molecular Sciences
ISSN 1422-0067 www.mdpi.com/journal/ijms Article

Computational Docking of Antibody-Antigen Complexes, Opportunities and Pitfalls Illustrated by Influenza Hemagglutinin
Mattia Pedotti †, Luca Simonelli †, Elsa Livoti and Luca Varani * Institute for Research inBiomedicine, via Vela 6, 6500 Bellinzona, Switzerland; E-Mails: mattia.pedotti@irb.unisi.ch (M.P.); luca.simonelli@irb.unisi.ch (L.S.); elsa.livoti@irb.unisi.ch (E.L.)

These authors contributed equally to this work.

* Author to whom correspondence should be addressed; E-Mail: luca.varani@irb.unisi.ch; Tel.: +41-91-820-0321; Fax: +41-91-820-0302. Received: 2 November 2010; in revised form: 22December 2010 / Accepted: 4 January 2011 / Published: 5 January 2011

Abstract: Antibodies play an increasingly important role in both basic research and the pharmaceutical industry. Since their efficiency depends, in ultimate analysis, on their atomic interactions with an antigen, studying such interactions is important to understand how they function and, in the long run, to design new moleculeswith desired properties. Computational docking, the process of predicting the conformation of a complex from its separated components, is emerging as a fast and affordable technique for the structural characterization of antibody-antigen complexes. In this manuscript, we first describe the different computational strategies for the modeling of antibodies and docking of their complexes, and thenpredict the binding of two antibodies to the stalk region of influenza hemagglutinin, an important pharmaceutical target. The purpose is two-fold: on a general note, we want to illustrate the advantages and pitfalls of computational docking with a practical example, using different approaches and comparing the results to known experimental structures. On a more specific note, we want to assess ifdocking can be successful in characterizing the binding to the same influenza epitope of other antibodies with unknown structure, which has practical relevance for pharmaceutical and biological research. The paper clearly shows that some of the computational docking predictions can be very accurate, but the algorithm often fails to discriminate them from inaccurate

Int. J. Mol. Sci. 2011, 12solutions. It is of paramount importance, therefore, to use rapidly obtained experimental data to validate the computational results. Keywords: antibody modeling; computational docking; influenza; hemagglutinin; antibody-antigen complexes


1. Introduction Individuals that recover from the attack of a pathogen have antibodies (Abs) capable of detecting and neutralizing the same pathogen in afuture encounter, usually conferring life-long protection from it. Detection and neutralization are initiated by the binding of these antibodies to antigens, often surface proteins, through specific atomic interactions between the antibody and the region of the antigen (Ag) that it recognizes (epitope). A better understanding of these interactions is expected to accelerate vaccine development, sincemost current vaccines are based on the generation of neutralizing antibody responses. If we understand the structural rules governing Ab-Ag interactions in a given virus, for instance, then we have the molecular basis to attempt to design and synthesize new epitopes to be used as vaccines, optimize the antibodies themselves for passive immunization or design new drugs mimicking the antibodies ortheir effect. In addition to pharmaceutical development, antibodies play an increasingly relevant role in basic research and industrial processes, where they are starting to be used as recognition elements sensitive to the presence of a given antigen. Designing and synthesizing new antibodies with desired properties would, therefore, have a profound impact, but we are very far away from being...
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