Biology Reference
In-Depth Information
Abstract
G protein-coupled receptors (GPCRs) are one of the most relevant superfamilies of
transmembrane proteins as they participate in an important variety of biological
events. Recently, the scientific community is witnessing an advent of a GPCR crys-
tallization age along with impressive improvements achieved in the field of com-
puter simulations during the last two decades. Computer simulation techniques
such as molecular dynamics (MD) simulations are now frequent tools to study the
dynamic behavior of GPCRs and, more importantly, to model the complex mem-
brane environment where these proteins spend their lifetime. Thanks to these tools,
GPCRs can be simulated not only longer but also in a more “physiological” fashion.
In this scenario, scientists are taking advantage of such advances to approach certain
phenomena such as GPCR oligomerization occurring only at timescales not reach-
able until now. Thus, despite current MD simulations having important limitations
today, they have become an essential tool to study key biophysical properties of
GPCRs and GPCR oligomers.
INTRODUCTION
G protein-coupled receptors (GPCRs) are transmembrane (TM) proteins involved in
a wide range of biological events such as transducing chemical signals, brain signal-
ing, modulating heart rate, or even mediating the immune response (
Katritch,
Cherezov, & Stevens, 2013
). They are the main protein superfamily in human
and mammalian genomes and all share a common structural feature: a seven-TM to-
pology (
Katritch et al., 2013
). The GPCR superfamily is nowadays one of the major
drug targets used in research and therapeutic activities (
Katritch et al., 2013
). The
boom of high-performance molecular dynamics (MD) simulations and the deposit
of the first GPCR crystal structures have finally enabled computational scientists
to simulate GPCRs for longer timescales in an attempt to understand the signaling
mode of these proteins (
Dror et al., 2011
). Likewise, the improved MD techniques
make it possible to model and simulate more complex membrane environments in
microsecond-regime simulations. Nowadays, one of the most challenging aspects
of simulating GPCRs is the study of GPCR-GPCR interactions. Whereas the dimer-
ization and oligomerization of GPCRs have been widely accepted by the scientific
community, the dynamics of such interaction remains largely elusive. Despite the
study of GPCR dimers and oligomers being still quite a challenging task in compu-
tational biosciences, MD simulations are arising as a helpful tool for this purpose.
Among different methods used in the simulation of biomolecular systems,
MD is the most commonly used technique. There are three main pillars of an MD
simulation, namely, the initial structure of the system, the force field, and the
MD simulation software. The initial structure is represented by the Cartesian coor-
dinates of the initial position of the whole system, for example, a Protein Data Bank
(PDB) file or a homology model, along with the network of connections that defines
