Biomedical Engineering Reference
In-Depth Information
correction to minimize basis set superposition error [
124
]. Due to the large molec-
ular system, HF/6-31G calculations coupled with intermolecular interaction
calculations can be successfully applied to study mechanistic aspects of
benzothiazepine class of calcium channel blockers. [
125
]
6.2 Applications of QM/MM Method
Due to the large size of ion channels, quantum chemical calculations of the type
describe previously cannot be applied to the full protein-complex at present.
However, recently more accurate molecular modeling of larger molecules, such
as in molecular biology and surface chemistry, has become feasible due to
developments in computational chemistry such as the hybrid quantum mechanics/
molecular mechanics (QM/MM) technique. This method is becoming increasingly
popular for modeling large molecular systems. In this approach, a large molecular
system can be partitioned into a small model system for the chemically important
active site, where a reaction or binding event occurs, and a large model system for
chemically inactive part. The active site is treated at a high level of quantum
calculation with more accurate methods, while the chemically inactive part is
modeled using only a molecular mechanics method.
To discover insight into how the K
+
channel promotes ion conduction was
provided by the structure of the KcsA potassium channel in complex with a
monoclonal Fab antibody fragment at 2.0
˚
resolution [
126
]. The electronic struc-
ture of the selectivity filter of KcsA potassium channel was investigated by density
functional theory (DFT/BLYP) and QM/MM methods. The electronic distributions
were then analyzed in terms of: (a) Wannier functions, (b) local dipole moments of
cations and ligands and (c) atoms in molecules analysis on the electronic structure
calculations obtained from the QM/MM simulations [
127
].
Another example is a cation-
interaction in ion channels that can discriminate
sodium channels that are either sensitive to tetrodotoxin (TTX). This structure was
further refined by a mixed-mode QM/MM optimization in which the Tyr401 side
chain and TTX were treated at the QM level (HF/6-31G*), and the rest of the
structure was treated at the MM level (OPLS2001 force field) with water repre-
sented as a continuum [
123
]. To address the question about the ionization state of
the Glu71/Asp80 residues of the KcsA potassium channel, QM/MM simulation
scheme was used where the two residues and their surroundings were treated by first
principle MD while the rest of the protein and environment was described at the
force-field level [
128
].
Moreover, QM/MM calculations can be used to compute the molecular electro-
static potential (MEP) inside the selectivity filter of the KcsA potassium channel.
An effective procedure is proposed to refine the charge parameterization of a force
field to reproduce a QM/MM reference potential along an MD trajectory [
129
].
More importantly, the QM/MM method has been successfully applied to assist the
development of improved force fields for ion channel studies. QM/MM simulations
p
