Biology Reference
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influence the range, diversity, and performance by which extracellular signals are
transferred to G proteins in the process of receptor transduction. As a consequence,
the control of oligomer formation and signaling will be a powerful pharmacological
tool. In order to design substances that modify GPCR dimer functioning, a few
conditions must be fulfilled. Firstly, it is needed to determine that oligomerization
takes place between particular receptors; secondly, that the oligomer has phar-
macological importance; and thirdly, that the availability of the oligomer three-
dimensional (3D) structure is required (
Kaczor & Selent, 2011
). Dimerization of
GPCRs is studied with experimental approaches, such as FRET and BRET (
Kaczor
& Selent, 2011
), and computational methods (
Selent & Kaczor, 2011
). Molecular
modeling approaches can be classified into sequence- and structure-based methods.
The first group is based on the GPCR sequence analysis performed in order to detect
evolutionary changes of the GPCR interfaces. Structure-based methodologies are a
potent complement to sequence-based approaches and involve protein-protein dock-
ing and molecular dynamics (MD) techniques as well as electrostatics analysis with
adaptive Poisson-Boltzmann solver (APBS) and normal mode analysis (NMA).
The aim of this chapter is to present a background, examples of applications, and
some technical aspects of structure-based molecular modeling approaches to study
GPCR oligomerization.
5.1
PROTEIN-PROTEIN DOCKING
While small-molecular docking is a well-established molecular modeling method
(the first truly successful docking method DOCK was published in 1982 by
Kuntz, Blaney, Oatley, Langridge, & Ferrin, 1982
), protein-protein docking is quite
often an ignored method. Somehow surprisingly, protein-protein docking is as old
method (or even older) as traditional small-molecular docking, as the first true ex-
ample of protein-protein docking originates to as early as 1970s (
Wodak & Janin,
1978
). Currently, protein-protein docking is a well-established method, albeit not
as widely used as small-molecular docking. Although one could easily believe that
the performance of protein-protein docking is far below the small-molecular dock-
ing, an excellent review by
Janin (2010)
clearly does not support this assumption. In
the past nine years, 42 protein-protein complexes have been modeled under the
CAPRI (critical assessment of predicted interactions) experiment and of these com-
plexes only 6 have not been successfully modeled.
In protein-protein docking, a common assumption is that protein-protein inter-
action
can be modeled based on shape complementarity and using simplified amino
acid models (in a similar fashion as typically used in early day molecular mechanics
united-atom force fields). While originally most of the protein-protein docking
methods were based on rigid-docking approach, currently most of the methods
are able to accommodate at least protein side-chain flexibility. Flexibility is clearly
a critical point to increase the quality of protein-protein docking, as in the CAPRI
