crystallographic water molecules in the binding site of PI3Kδby
setting the optionIgnore watersto false.
Finally, the sectionAdvanced optionsis used to specify output
parameters, such as the maximum number of binding modes gen-
erated for each docking analysis, the extension of the conforma-
tional search procedures and the energy gap between the accepted
solutions. In general, setting higher values increases the probability
of finding likely solutions; however, it also increases computational
time. Therefore, we should always consider the available computa-
tional resources and the desired duration of the simulation to set
those parameters appropriately. Because we are dealing with only
one compound with low structural complexity, we can use the
maximum allowed values.
The Chimera interface to AutoDock Vina allows the molecular
docking to be run locally or to use a remote web server. Because
you downloaded Vina (http://vina.scripps.edu/download.html)
on your machine, use thelocaloption at theExecutablesection,
and select the Vina program location using theBrowseoption.
Finally, run the molecular docking simulation by clickingOK.
This procedure will generate therunningmessage in the status bar.3.2.4 Visualizing Results After running the molecular docking procedure, the ViewDock
window containing the scores of the predicted binding solutions
will open (Fig.2b). Each 3D conformation can be observed by
clicking on the corresponding score. Each value corresponds to the
predicted binding energy, in kcal/mol, calculated by the AutoDock
Vina scoring function. Therefore, the more negative the value, the
higher the probability of the ligand–receptor interaction occurring
in experimental tests. Additionally, the hydrogen bonds for each of
the predicted ligand–receptor complexes can be observed in the
ViewDock window by selecting the following option:HBonds!
Add Count to Entire Receptor. In the new window, enableLabel
H-bond with distanceandRelax H-bond constraints,change the
parameterLine widthto 10, and selectinter-modelin the section
Find these bondson the right. Leave all the remaining options
disabled, and clickOK. Next, to explicitly display the atoms of the
receptor binding site, go toActions!Atoms/Bonds!showand
then toActions!Ribbon!hideon the main menu of Chimera.
At this point, we should see a colorful line displaying the
ligand–receptor hydrogen bonds (Fig.3a). If your simulation led
to the correct prediction, you should observe a distinct interaction
between the backbone valine 628 amino group and the ligand N3
nitrogen of the 7H–purine ring (Fig.3a). Explore the other pre-
dicted conformations, and look for the interactions in each
complex.
Having identified all the predicted conformations, we can com-
pare these solutions with the crystallographic binding mode of
Molecular Docking and Structure-Based Virtual Screening 43