Biomedical Engineering Reference
In-Depth Information
spectroscopy or compared to biochemical activity, however, for the uncomplexed
channel model; channel conductance is used as the experimental reference [
72
].
The conductance value (
g
) as obtained from (1) depends on the resistivity (
), pore
r
length (
L
), and pore radius (
r
):
¼
p
r
2
g
¼
1
=
R
p
þ
R
A
=
½
ð
L
þ
0
:
5
r
Þ
:
(1)
r
p
The unknown structures of the complex of blockers and ion channels can also be
predicted by MD simulations. The initial configuration of the complex is usually
obtained by molecular docking, before relaxation by MD simulations, as
exemplified in the case of the homology complex model of human voltage-gated
hERG potassium channel and its blockers [
43
]. When a poor scoring function from
docking cannot discriminate strong and weak blockers of Sertindole and its
derivatives against the open-state hERG channel, short MD simulations of 250 ps
was found to helpfully remove steric and electrostatic clashes, yielding more
reliable models [
43
]. The complex with top score from docking was sometimes
selected before merging the model into the lipid bilayer followed by standard MD
simulations [
75
]. The simulations not only relax the complex model but also help to
reveal the key residues involved in the binding and blocking mechanism. Validation
of the complex model can be achieved using relative thermodynamics properties
and experimental affinities such as
DD
G
LIE
versus
DD
G
IC50
[
43
].
3.2 MD Simulations to Describe Ion Channel Blocking
Mechanism
MD simulations not only help to elucidate aspects of the interaction between a
blocker and an ion channel, but they can also help to describe the internal motions
and thermodynamics properties of blocking process, revealing additional aspects of
the blocking mechanism. Investigation of the voltage-gated potassium (Kv1) chan-
nel subtypes by the scorpion maurotoxin (MTX) was carried out by Brownian
dynamics (BD) simulations at 500 K under rigid body conditions. Thus, this
predicted that MTX preferred the Kv1.2 over Kv1.1 and Kv1.3 by 4-7 kcal/mol
from the more favorable electrostatic interaction between triplet contacts. Critical
residues associated with MTX blockage are all positively residues i.e. Lys23,
Lys27, and Lys30, which interact with three negatively charged aspartic acid
residues of Kv1.2 [
76
]. Novel blocking patterns of gambierol toxin against Kv1.5
potassium channel, which has not been reported from experiment, found that after
the gambierol was docked into the Kv1.5 and the complex was inserted into POPC
membrane with solvated waters, that the gambierol interacted with different
subunits of Kv1.5 tetramer as described above, as well as residues of Thr480,
Val505, Val512, Val516 [
75
].
Reportedly key residues in the experimentally undetermined model of the
7
nicotinic acetylcholine receptor we also predicted through MD simulations [
47
]. In
a
