Biology Reference
In-Depth Information
experiment most of the failures are connected with protein conformational changes
upon protein-protein interaction.
Another typical approach in protein-protein docking is that protein complexation
will occur in biological solvent, not inside the cell membrane as in the case of
GPCRs. As many of our potential protein-protein complexes are located in mem-
brane environment, this will surely affect the performance of protein-protein docking
methods. While earlier-mentioned CAPRI experiment is typically targeting nonmem-
brane protein-protein complexes, in a recent study (
Kaczor, Selent, Sanz, & Pastor,
2013
), it was shown that membrane environment needed for GPCR docking is indeed
a major problem requiring future work.
Like in the case of small-molecular docking, scoring functions are of utmost
importance for the quality of the results. Commonly, scoring functions used in
protein-protein docking are based onweighted sums of different parameters including
typically chemical and physical properties important for protein-protein interactions.
In addition, different geometric properties and atom-atom or residue-residue poten-
tial are evaluated. Desolvation effects are usually taken into account indirectly, but it is
also possible to calculate this term using explicitly approach (although this latter
is quite slow approach).
Docking experiments to create GPRC dimers (both homo- and heterodimers) has
not been reported often in recent years, as the phenomenon of GPRC dimerization
has gained attention only during the last few years. One of the first reviews devoted
just to GPCR dimerization is just 15 years old (
H´bert & Bouvier, 1998
), and even at
the moment (May 2013), PubMed search with keywords “GPRC dimerization dock-
ing” yields only eight publications. In spite of this (or actually due to this), it is im-
portant to look at those topics, which are important for usage of protein-protein
docking programs if and when those are utilized to study the dimerization of GPCRs.
In this part, we aim to give some general guidelines regarding available programs,
preparation of protein structures (docking partners) prior to the docking exercise and
analysis of the docking results. This text should not be taken as a cooking topic recipe
for protein-protein docking but more as a practical checklist to support someone who
is willing to try first time protein-protein dockings within the realm of GPCRs.
5.1.1
Available docking programs
Most (but surely not all) important protein-protein docking programs and their
performance to recreate protein-protein complexes found in transmembrane
environment have been analyzed by
Kaczor et al. (2013)
. Of the tested methods,
GRAMM-X (
Tovchigrechko & Vakser, 2006
) method gave the best overall perfor-
mance with RMSD lower than 0.7
˚
in 8 out of 12 cases. The problem was that with
four cases (pdb-ids: 2I37, 3CAP, 3OE9, and 4DJH), which all where seven-
transmembrane receptors, RMSD was at least 9
˚
, which basically equals to total
failure to detect the true protein-protein interaction mode. The even worse topic
is the fact that all the tested methods were no better (with the only exception HAD-
DOCK (
De Vries, van Dijk, & Bonvin, 2010
) in the case of chemokine receptor
