Guidelines To Predict Binding Poses of Antibody–IntegrinComplexes
2020
Integrins are cell adhesion receptors
that transmit bidirectional
signals across the plasma membrane. They are noncovalently linked
heterodimeric molecules consisting of two subunits and act as biomarkers
in several pathologies. Thus, according to the increase of therapeutic
antibody production, some efforts have been applied to produce anti-integrin
antibodies. Here, we purposed to evaluate methods of generation and
identification of the binding pose of integrin–antibody complexes,
through protein–protein docking and molecular dynamics simulations,
and propose a strategy to assure the confidence of the final model
and avoid false-positive poses. The results show that ClusPro and
GRAMM-X were the best programs to generate the native pose of integrin–antibody
complexes. Furthermore, we were able to recover and to ensure that
the selected pose is the native one by using a simple rule. All complexes
from ClusPro in which the first model had the lowest energy, at least
5% more negative than the second one, were correctly predicted. Therefore,
our methodology seems to be efficient to avoid misranking of wrong
poses for integrin–antibody complexes. In cases where the rule
is inconclusive, we proposed the use of heated molecular dynamics
to identify the native pose characterized by RMSDi <0.5 nm. We
believe that the set of methods presented here helps in the rational
design of anti-integrin antibodies, giving some insights on the development
of new biopharmaceuticals.
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