Biophys J, June 1998, p. 2744-2745, Vol. 74, No. 6
NEW AND NOTABLE
Molecular Dynamics Simulations of Ion Channels: How Far Have We
Gone and Where Are We Heading?
Benoît
Roux
Groupe de Recherche en Transport Membranaire (GRTM),
Départements de Physique et Chimie, Université de
Montréal, C.P. 6128, Succursale Centre-Ville,
Montréal, Québec, H3C 3J7 Canada
 |
ARTICLE |
In this issue of the Biophysical
Journal, Tieleman and Berendsen report the results of a molecular
dynamics (MD) simulation of the pores formed by an Escherichia
coli porin in a fully hydrated explicit POPE bilayer. The
microscopic system includes the full OmpF trimer, 318 lipids (POPE),
and 12,992 water molecules for a total of 65,898 atoms. After an
equilibration period, the trajectory is generated for more than 1 nanosecond. By all standards, this is a monumental calculation of an
important biological system.
The publication of the paper of Tieleman and Berendsen is a good
opportunity to pause and look back at the impressive progress accomplished in computer simulations of biomolecular systems over the
years. Since the first dynamical calculation of a simple liquid of hard
spheres (Alder and Wainwright, 1957
), MD simulations have grown rapidly
in complexity: first molecular dynamics of liquid water (Rahman and
Stillinger, 1971), of a protein (McCammon et al., 1977), of an ion
channel (McKay et al., 1984), of a bilayer membrane (Egbert and
Berendsen, 1988), and of an ion channel in a membrane (Woolf and Roux,
1994). The present work by Tieleman and Berendsen offers a striking
example of how current MD simulations have reached the point where
atomic models can provide realistic representations of complex
biological systems. In the present paper, OmpF, a large transmembrane
ion channel, was simulated in a realistic model of a bilayer membrane.
In particular, the simulation shows the properties of the pore and its
water content. Around the pore constriction zone, the water dipoles are
highly ordered perpendicular to the channel axis; the diffusion
coefficients of water molecules inside the pore is greatly reduced.
Porins represent an important model system for studying ion channels at
the microscopic levels. Several aspects of the function of OmpF have
not been entirely elucidated and will probably require a combination of
experiments and calculations. In principle, MD simulations based on
detailed realistic atomic models can help to understand better the
function of these systems. Nonetheless, despite the progress in
computer simulations, theoretical investigations of ion channels are
still faced with particularly difficult and serious problems.
A first problem arises from the magnitude of the interactions involved.
The large hydration energies of ions, around 
400 kJ/mol for
Na+, contrast with the activation energies deduced from
experimentally observed ion fluxes, which generally do not exceed 10 kBT. This implies that the energetics of ion transport
results from a delicate balance of very large interactions. This raises
the question of the potential function and the influence of induced
polarization, which is usually neglected in current calculations. A
second problem arises from the time scales involved. The passage of one
ion across a channel takes place on a microsecond time scale and
realistic simulations of biological systems, which typically do not
exceed a few nanoseconds, are insufficiently short. Straight molecular dynamics still cannot account for the time scales of ion permeation, and specialized simulation methods must be used to investigate these
systems. A last difficulty is the translation of the results obtained
from a microscopic model into macroscopic observables such as channel
conductance and current-voltage relations (IV). How to go effectively
from MD to IV curves remains a fundamentally unresolved question.
Future progress in theoretical studies of ion transport will come from
efforts to push forward the limits in three directions: improving the
potential function, developing appropriate simulation methods, and
formulating useful theoretical frameworks for establishing a link
between detailed trajectory and macroscopic quantities that are
measured experimentally. An essential prerequisite for undertaking
meaningful studies based on atomic models is the availability of a high
resolution structure. The present work was made possible because the
structure of OmpF was determined by x-ray crystallography (Cowan et
al., 1992). The very recent determination of the structure of the K
channel from Streptomyces lividans will provide another very
exciting system to investigate ion permeation (Doyle et al., 1998).
Meanwhile, it is stimulating to read about this impressive calculation.
| |
FOOTNOTES |
Received for publication 20 April 1998 and in final form 21 April 1998.
Address reprint requests to Benoit Roux, Professeur, Departement de
Physique, Departement de Chimie Universite de Montreal, Case Postale
6128, Succursale Centre-Ville, Montreal, Quebec Canada H3C 3J7. Tel.:
514-343-7105 (office/bureau); Tel.: 514-343-6111 (ext. 3953) (lab);
Fax: 514-343-7586; E-mail:
rouxb{at}plgcn.umontreal.ca.
| |
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Biophys J, June 1998, p. 2744-2745, Vol. 74, No. 6
© 1998 by the Biophysical Society 0006-3495/98/06/2744/02 $2.00
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