nergy scales have
made computations infeasible. Now, using the computational power of the Cray XT
and the IBM Blue Gene leadership-class computers, researchers are gaining new
insights into the mechanisms of these electro-mechanical marvels.
The cell membrane represents the physical and
functional boundary between living organisms and
their environment. Membrane-associated proteins
play an essential role in controlling the bidirectional
flow of material and information. As such, they can
be viewed as nanoscale molecular machines able to
accomplish complex tasks. Ion channels, a highly
specific class of such proteins, regulate the perme-
ation of small ions in and out of the cell. These pro-
teins can switch between different conformational
statesa process known as gatingthereby
allowing or blocking the passage of ions across the
cell membrane in response to various cellular sig-
nals (figure 1).
Voltage-gated potassium channels, or Kv chan-
nels, are involved in the generation and spread of
electrical signals in neurons, muscle, and other
excitable cells. To open the gate of a channel, the
electric field across the cellular membrane acts on
specific charged amino acids that are strategically
placed in the protein in a region called the voltage
sensor. In humans, malfunction of these proteins,
sometimes owing to the misbehavior of only a few
atoms, can result in neurological diseases.
A long-term endeavor of research in biophysics
is to understand the workings of these ion channels
and to predict their function. A wealth of experi-
mental data exists from a wide range of approaches,
but its interpretation is complex. One must ulti-
mately be able to visualize atom by atom how these
tiny mechanical devices move and change their
shape as a function of time while they perform. This
goal has long remained elusive.
Recently, however, a team of researchers from
Argonne National Laboratory, the University of
Chicago, the University of IllinoisChicago, and the
University of Wisconsin has used high-perform-
ance computing to break new ground in under-
standing how these membrane proteins work.
Exploiting state-of-the-art developments in molec-
ular dynamics and protein modeling, the team has
constructed models of Kv voltage-gated channels
and run them on the Cray XT and IBM Blue Gene
leadership-class computers.
Being able to run on these top computers is
essential for this work, says Dr. Benoit Roux, a com-
putational scientist who holds a joint appointment
at Argonne and the University of Chicago. The time
22
S
C I
D A C R
E V I E W
F
A L L
2 0 0 8
W W W
.
S C I D A C R E V I E W
.
O R G
SIMULATION
Provides Key to
the Mystery of
MOLECULAR Machines
A long-term endeavor of
research in biophysics is to
understand the workings of
these ion channels and to
predict their function.
Recently, a team of
researchers has used high-
performance computing to
break new ground in
understanding how these
membrane proteins work.
Fa08 22-27 Membrane.qxd 8/29/08 3:06 PM Page 22 Closed State
Open State
Voltage-Sensing
Domains
(Gate Open)
(Gate Closed)
Membrane
Pore Domain
V < 0
V > 0
23
S
C I
D A C R
E V I E W
F
A L L
2 0 0 8
W W W
.
S C I D A C R E V I E W
.
O R G
Figure 1.
Schematic of the function of a voltage-gated ion channel. At rest, the normal cellular potential of a living cell is negative and the potassium
channels are closed. When the cellular membrane is depolarized and the potential becomes positive, the channel is activated and can conduct K
+
ions
(represented by the yellow arrow, right). The conformation change from the closed to the open state is driven by the movement of the positively-charged
amino acids (orange + symbols) located in a region of the protein called the voltage sensor surrounding the central ionic pore.
and energy scales of the underlying molecular
processes are just within reach of the computational
capabilities of such leadership-class computers.
Enabling New Science
In earlier work the team had assessed a model of Kv
channels in mammalian cells. Under a grant from
the U.S. Department of Energy Innovative and
Novel Computational Impact on Theory and Exper-
iment (INCITE) program in 2007, the researchers
were able to extend this work to more complex
membrane proteins, taking advantage of the com-
putational power of the 5.7-teraflop Blue Gene/L
(BG/L) at the Argonne Leadership Computing Facil-
ity (ALCF) and the 100-teraflop Cray XT3 at Oak
Ridge National Laboratory.
Their study has already produced exciting results.
For example, the researchers have, for the first time,
confirmed the hypothesis that the electric field con-
trolling the voltage-gating is focused over a particu-
lar area, rather than spread throughout the whole
thickness of the cellular membrane. As a result of
these initial successes, Dr. Roux recently received an
allocation of five million hours under the 2008
INCITE program to continue this research on the
Blue Gene/P at Argonne and the Cray at Oak Ridge.
The practical applications of this work are signif-
icant. For example, the research in ion channel
mechanisms may help identify strategies for treat-
ing cardiovascular disorders such as long-QT syn-
drome, which causes irregular heart rhythms and is
associated with more than 3,000 sudden deaths each
year in children and young adults in the United
States. Moreover, the studies may help researchers
find a way to switch or block the action of toxins
such as those emitted by scorpions and beesthat
plug the ion channel pores in humans.
An Integrated Approach
One of the teams first steps in elucidating the volt-
age-gating mechanism was to develop models of a
Kv channel in both the closed (resting) and open
(activated) states. Of special importance in this work
was experimental data, reported in the literature, on
the x-ray crystallographic structure of a voltage-
gated potassium channel, the Kv1.2 channel from
rat brain, which provided the first atomic resolution
structure of a voltage-gated potassium channel in
the open state. A previous study had determined the
x-ray structure of the potassium channel KvAP from
an archaebacterium, although it was soon realized
that the protein was distorted in those crystals.
The researchers also drew on recent major
advances in high-resolution de novo prediction of the
three-dimensional structure of proteins from amino
acid sequences. In particular, the Rosetta membrane
method was extended and used by Dr. V. Yarov-
Yarovoy, one of the team collaborators at the Uni-
versity of Washington, for modeling the
voltage-sensing domain conformations of Kv
The practical applications
of this work are significant.
For example, the research
in ion channel mechanisms
may help identify strategies
for treating cardiovascular
disorders such as long-QT
syndrome.
B. R
OUX
, U. C
HICAGO
/ANL
Fa08 22-27 Membrane.qxd 8/29/08 3:06 PM Page 23 M O L E C U L A R B I O L O G Y
channels. This method is based on the assumption
that the native state of a protein is at the global free
energy minimum. A large-scale search of confor-
mational space for protein tertiary structures is car-
ried out to select structures that are especially low
in free energy for a given amino acid sequence.
The team also capitalized on advances in molec-
ular dynamics. This computational approach
involves simulating the dynamical motions of all the
atoms of a system as a function of time (sidebar
Advanced Computational Techniques). Introduced
in the late 1950s for studies of simple liquids of hard
spheres, molecular dynamics has matured and
grown rapidly in complexity over the years, with
simulations of liquid water, proteins, lipid bilayer
membranes, and in recent years, even a complete
viral life form.
Large-Scale Simulations
Armed with this structureprediction algorithm
and with advanced modeling methodology, the
team constructed a complete model of the KvAP
voltage-gated potassium channel. To correct for the
distortion observed in the x-ray structure of earlier
studies, the model exploited electron paramagnetic
resonance experimental data measured in the lab-
oratory of the University of Chicagos Department
of Biochemistry and Molecular Biology.
The researchers ran their simulated system, which
consisted of the channel embedded in a lipid bilayer
surrounded by an aqueous salt solution, on the
2,048-processor BG/L at the ALCF (figure 2). The
simulations were generated by using the parallel
program Nanoscale Molecular Dynamics (NAMD),
a parallel code developed at the University of Illi-
noisUrbana-Champaign in the lab of Dr. Klaus
Schulten, one of the teams researchers. The code
is designed for high-performance classical simula-
tion of large biomolecular systems and can scale up
to thousands of processors on high-end parallel
platforms such as BG/L. The optimized version of
NAMD used on the BG/L at Argonne was provided
by IBM. Preliminary analysis indicated that the
native arginine (a common amino acid) residues in
the voltage sensor are more hydrated and located
farther from the center of the membrane than pre-
viously indicated by the use of traditional spin labels
and electron paramagnetic resonance spectroscopy.
24
S
C I
D A C R
E V I E W
F
A L L
2 0 0 8
W W W
.
S C I D A C R E V I E W
.
O R G
Figure 2.
Atomic model for the simulation of the KvAP channel in a lipid membrane. The model represents the channel in an open activated state
as determined by electron paramagnetic resonance expe