Biology Reference
In-Depth Information
such system. The force field is used to describe the type of interaction existing be-
tween each of the atoms or a group of atoms connected in the initial structure. While
in all-atom simulations all single atoms in the systems are represented, coarse-
grained (CG) structures and force fields use a reduced level of description by
mapping specific sets of atoms in one group. CHARMM (
MacKerell et al., 1998
),
AMBER (
Cornell et al., 1995
), GROMOS (
Christen et al., 2005
), and OPLS
(
Jorgensen, Maxwell, & Tirado-Rives, 1996
) are force fields commonly used in
all-atom MD simulations, whereas the MARTINI force field (
Marrink, Risselada,
Yefimov, Tieleman, & de Vries, 2007
) is the most widely used force field in CG
simulations.
Although most of the published work on MD simulations of GPCRs typically
uses GROMACS (
Hess, Kutzner, van der Spoel, & Lindahl, 2008
), NAMD
(
Phillips et al., 2005
), ACEMD (
Harvey, Giupponi, & Fabritiis, 2009
), or CHARMM
(
Brooks et al., 1983
), currently, there exist a vast number of MD engines developed
for this purpose. In essence, MD engines use the aforementioned force field to nu-
merically solve the classical equations of motion through a sampling algorithm. The
forces needed to solve these equations are obtained from the potential energy func-
tion, which depends on the position of the atoms of the system. Despite there are
different force fields, the form of the potential energy function is similar in most
of the ordinary ones and consists of a sum of both bonded (e.g., bond, angles, and
rotation) and nonbonded terms (e.g., van der Waals and electrostatic interactions).
The intention of this chapter is providing an overview of the methodology and the
analysis approaches currently used for MD simulations of membranes and GPCR
monomers or heteromers in their native-like environment. Thus, firstly, we focus
on the simulation of biological membranes; secondly, we describe the process of
modeling and simulating GPCR monomers embedded in membranes; and, lastly,
we discuss current approaches to study GPCR oligomerization by means of MD
simulations.
4.1
MEMBRANES
4.1.1
The importance of modeling physiological membranes
As all TM proteins, GPCRs live permanently surrounded by membrane lipids. They
look just like plain membrane solvent or a physical barrier for the whole set of pro-
teins therein confined. Indeed, the amphipathic character of membrane lipids enables
cells not only to segregate internal cell organelles but also to separate the whole cell
from the interior milieu. However, it is becoming more and more evident that con-
sidering the main role of lipids as being only structural is a misconception of the true
global mission of these molecules. Cells synthesize a colorful assortment of lipid
species across the body (
Van Meer, Voelker, & Feigenson, 2008
), generating cells
and tissues with specific lipid profiles. As a result of such segregation, cell mem-
branes have diverse biophysical properties (
Feigenson, 2007
) maintained through
a careful exchange of lipids between cell organelles and the plasma membrane. Im-
portantly, such lipid regulation also affects the composition of each leaflet of the
