the functional role of biomolecules. One of the transmembrane
(TM) proteins, such as G protein-coupled receptors (GPCRs),
provides an exemplary paradigm for allosteric proteins whose
basic functioning units are the communications between the two
poles of the seven TM helical bundle.
GPCRs are unarguably the most well-known pharmaceutical
target. They act as both gate-keepers and molecular messengers of
the cell converting extracellular signals to cellular activities. Struc-
turally, this receptor consists of a sevenα-helical membrane span-
ning domain (TM1–TM7) which connects the extracellular
environment to the cell interior, and thus, they are also known as
seven-transmembrane (7TM or heptahelical) receptors
[2, 3]. GPCRs respond to the binding of extracellular ligands
inducing a conformational change in the orthosteric binding site,
and this change extends via the 7TM scaffold into their intracellular
domain, subsequently leading to the binding and activation of
G-proteins or arrestins [4, 5]. Identifying the allosteric mechanism
of proteins is important not only for understanding their functional
role but also as a base for structure-based drug design.
The mechanisms of protein allostery are difficult to be revealed
from the static snapshots provided by the X-ray crystallographic
structures. Therefore, molecular dynamics (MD) simulation has
emerged as a valuable tool in the study of allostery, because they
can capture the protein’s motion in full atomic detail. This method
has a unique strength of presenting the atomistic details of a pro-
tein’s dynamic behavior on several timescales ranging from femto-
second to seconds, thus acting as a “computational microscope”
[6]. However, even with the atomistic details of three-dimensional
(3D) structure at hand, determining the structural basis for allo-
stery often proves challenging. Currently, several methods are avail-
able to reveal networks or paths of communication in protein
ensembles (collected by MD simulation technique). Recent studies
have addressed the microscopic mechanism of protein allostery by
applying the strategies of network or community analysis in con-
junction with MD simulation on model systems [7–9].
When a complex system is simplified into a network (graph),
which is represented as “nodes” (vertices) and “edges” (links), the
architecture of the network allows one to extract the key properties
of the entire system and its individual elements [10]. The network
analysis method was first developed for analyzing social phenom-
ena, but now is popularly used in several research areas, including
statistical physics, particle physics, computer science, and econom-
ics. Recently, it has also been applied in several fields of biology for
the investigation of protein–protein interactions, metabolic net-
works, disease networks, drug–target networks, etc. [10–12]. The
3D structures of proteins can also be represented as networks,
where amino acid residues are considered as nodes and their inter-
actions as edges [13]. This residue interaction network has been456 Shaherin Basith et al.