Biology Reference
In-Depth Information
structure is inserted into a membrane system, solvated, and ionized (neutralized) up to
a physiological concentration. Nowadays, tremendous efforts have been undertaken to
model native-like cell membranes instead of just monocomponent membranes. A de-
tailed description of building, simulating, and analyzing membranes (e.g., hydropho-
bic mismatch) is given in the chapter 4.
Unfortunately, all-atom simulations are linked to certain limitations in system
size and timescale and make the study of physiological relevant invents such as
receptor oligomerization not feasible. An alternative approach is provided by apply-
ing CGMD as recently shown in an elegant study by
Periole et al. (2007, 2012)
.
Thereby, the all-atom system is simplified by combining groups of atoms into
one single beat, which allows simulating much longer timescales compared to all-
atom systems.
All in all, using modern computing infrastructure (parallel computing), we can
simulate the evolution of GPCR target structures in a native-like environment
(all-atom or coarse-grained) up to microseconds. Importantly, replicates from individ-
ual starting structures are inevitable to proof the relevance of an observed dynamic
event.
Readers who would like to learn more about the technical details should refer to
the chapter 4 within this edition.
5.3
NORMAL MODE ANALYSIS
5.3.1
Background and examples of applications
As discussed earlier, molecular modeling techniques supply effective approaches for
investigation of dynamics of proteins. Besides MD simulations, NMA can be used
for this purpose, in particular when the protein is relatively big (several
thousand amino acids) and the timescale of the dynamical events of interest is longer
than what MD simulations can reach, typically a few nanoseconds (
Hollup,
Salensminde, & Reuter, 2005
). NMA approach assumes that the vibrational
normal modes exhibiting the lowest frequencies (also named soft modes) describe
the largest movements in a protein and are the ones functionally relevant (
Hollup
et al., 2005
). NMA calculations are based on the diagonalization of the matrix of
the second derivatives of the energy with respect to the displacements of the
atoms, in mass-weighted coordinates (Hessian matrix) (
Skjaerven, Jonassen, &
Reuter, 2007
). The eigenvectors of the Hessian matrix are the normal modes, and
the associated eigenvalues are the squares of
the associated frequencies
(
Skjaerven et al., 2007
).
There are not many examples of application of NMA to GPCRs. These include a
study of conformational changes occurring in the rhodopsin monomer upon activa-
tion (
Isin, Rader, Dhiman, Klein-Seetharaman, & Bahar, 2006; Niv, Skrabanek,
Filizola, &Weinstein, 2006
), an analysis of the low-frequency modes of cone opsins
(
Thirumuruganandham & Urbassek, 2009
), studies of the activation of the ghrelin
