Ion Channel Caught In The Act | Chemical & Engineering News http://cen.acs.org/articles/90/web/2012/04/Ion-Channel-Caught-Act.

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April 12, 2012 | Latest News

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Computational Biochemistry: Simulation tour de force visualizes protein’s opening and closing
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Department: Science & Technology Precise Nanoparticle Arrays Could

Keywords: molecular dynamics, ion channel Herald Exotic Electronics

The Mediterranean Beneath The

Surface
[+]Enlarge One of the most extensive
New Class Of Superbases
biomolecular simulations ever
has allowed researchers to Covalent Ties Reversed
visualize the opening and
closing of a voltage-gated
potassium ion channel for the
first time.

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Ion Switch Closure
heart disease, paralysis, Channel closure occurs early in this visualization, Potassium Ions On The Move
migraine, and other conditions taken from inside the cell looking out. Voltage-sensing Renaissance Men
caused by ion-channel domains are mostly green, S4 helices are red, linker
Ion Switch malfunctions. The work also helices are orange, pore gate domains are white, and
As potassium ion channel closes, S4 helices in pore constriction is blue.
shows that a previously
voltage-sensing domains (VSDs, one of four shown) Credit: Courtesy of D. E. Shaw Research
twist down toward the cell interior. S4’s linker helices unattainable level of computer
then loosen their hold on pore gate domains (two of power is becoming available
four shown), allowing pore closure. In channel to help scientists better
opening, S4s twist upward, causing linkers to pull pore understand biomolecules.
gate domains open. Insets show (from above) all four
VSDs (circles), pore gate domains (squares), and
Structures of voltage-gated
linkers (lines). Also shown are key VSD phenylalanine
and basic (+) and acidic (-) S4 side chains. ion-channel open states have
been obtained, and many
clever experimental and theoretical studies have revealed much about channel
behavior. But closed-state structures have remained elusive, making it difficult to
nail down the channels’ overall mechanism.

Now, computational biochemist David E. Shaw of D. E. Shaw Research, in

New York City, and Columbia University and his coworkers including Morten Ø.
Jensen have used a customized computer called Anton to perform all-atom
calculations on a long-enough time scale to simulate ion-channel opening and
closing (Science, DOI: 10.1126/science.1216533). The study was internally
funded by Shaw Research and not supported by any government grants.

The study of a system of more than 100,000 atoms was made possible by
Anton’s ability to perform molecular dynamics simulations about 100 times faster
than those carried out by any other computer. The longest simulation time in the
new study is 230 microseconds, whereas comparable simulation times on other
computers have been about 10 microseconds at most.
Pore-Opening Mechanism
S4 helix (red) moves down into the cell relative to the
rest of the voltage-sensing domain (mostly yellow and
green) as pore opening occurs. Basic and acidic
amino acid residues (stick structures) and a key
phenylalanine (hexagon) are shown explicitly.
Credit: Courtesy of D. E. Shaw Research

1 of 2 2012-04-12 23:40
Ion Channel Caught In The Act | Chemical & Engineering News http://cen.acs.org/articles/90/web/2012/04/Ion-Channel-Caught-Act.html

To make their computationally demanding simulations of channel opening and

closing fast enough to be practical, the Shaw group applied membrane voltages
several times higher than normal. That maneuver could spark controversy about
whether the simulations elicited realistic channel behavior.

S4 helices on each of the channel’s four voltage-sensing domains are the main moving parts. The simulation shows them twisting
as they open and close the channel. In work suggesting possible biomedical applications of the study, the group also simulated the
activity of a channel with a known heritable mutation and proposed a mechanism for its aberrant flow, which is believed to cause
heartbeat irregularities and neurological problems.

“Amazing!” said ion-channel expert Frederick J. Sigworth of Yale School of Medicine after viewing a movie of the normal
process. “It’s like seeing for the first time something that until now has existed only in imagination. There are going to be things
shaken out about whether Shaw and company got the details right, but it’s very impressive that they were able to put together a
pretty convincing physical system and let it run.”

The new findings agree with a general consensus about the mechanism that has developed in the past couple of years, Sigworth
and others tell C&EN. However, researchers disagree or are uncertain about some mechanistic details, such as how much S4
moves and whether or not it twists. Shaw’s simulation could help resolve such points of contention.

Chemical & Engineering News

ISSN 0009-2347
Copyright © 2012 American Chemical Society

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