Biomedical Engineering Reference
In-Depth Information
aspects of MD simulations as applied to ion channels blockers. There are 71
unrelated structures of ion channels reported in the protein data bank. Species,
mutation, and ligand complex differences can generate several hundred structures,
for instance, few 3D structures were solved experimentally; voltage-gated potas-
sium channel [
1
,
62
-
64
], proton channel [
65
]; ligand-gated ion channels [
66
-
69
];
acid-sensing ion channel [
70
].
Because of the lack of suitable experimental structures, homology modeling is
generally required before exploring the interactions between an ion channel blocker
and its target. MD simulations are essential for the evaluation of these models of ion
channels, while additional information can be associated from mutagenesis experi-
ment. Gating or blocker binding mechanisms can also be revealed using MD
simulations. MD simulations allow us to explore the configuration of the entire
protein, thus demonstrate the conformational change of the channel gate, which is
of course key to the function of ion channels. To observe the physiological
properties of the ligand/ion channel complex, MD simulations are often used in
conjunction with molecular docking methods.
3.1 Homology Modeling of Ion Channel Models
Acquiring crystallographic structures of ion channels is a major challenge due to the
difficulty in obtaining suitable protein crystals for X-ray diffraction. Only a few
proteins are available, for example, the bacterial KvAP channel [
71
] and the
acetylcholine binding protein (AChBP) of
Lymnaea stagnalis
[
68
]. The unknown
structures of targets, such as hERG potassium (Kv) channel, p7 of Hepatitis C, and
b
-amyloid aggregation, can only be studied using models derived from homology
modeling and MD simulations. As the formation of the ion channel is generally
based on protein-protein interactions, we have selected a small number of the
systems to be reviewed, for example, bundles of tetramer, pentamer and hexamer,
which are typically formed to function as the ion channel.
The
) is proposed to aggregate into a tetramer or pentamer
quaternary structure according to the favorable electrostatic interactions between
the monomers. The model adopts a slightly distorted
C4
symmetry structure when
monomers rotate their acidic face of itself to the basic face of neighboring mono-
mer, driven by inter-subunit interaction with lysine, glutamic, aspartic, histidine,
and tyrosine [
72
]. Viral protein U in HIV-1 (Vpu) exists in high stability
homopentameric bundles where tryptophans residues are directed out of the pore
facing the lipid layer [
73
]. Simulations of tetrameric bundles of hERG potassium
channel provide good agreement with experimental observation [
74
]. A well-
constructed model must be maintained the structural stability during 10 ns of
simulations as indicated by the small root-mean-square fluctuations (RMSF) of
the C
a
atoms [
47
]. The benefit of these homology models is shown in docking
technique, which is an important process in drug design [
49
]. Validation of the
macrobiomolecular model
b
-amyloid peptide (A
b
is generally considered with the NOE from NMR
