Permeation of Ions Through Membrane Channels - Molecular Dynamics Studies


Because all electrical activities in the brain are regulated by opening and closing of ion channels, understanding their mechanisms at a microscopic level is a fundamental problem in biology. Making full use of some recent technological and conceptual advances, we are studying, using computer simulations, how ions navigate through a narrow pore formed by protein molecules. From the results of extensive computer simulations, we propose to deduce mathematically the inner working details of membrane channels, information that may lead us to find the causes of and, possibly, cures for many of the neurological and muscular disorders. The research projects we have embarked upon can only be carried out with fast supercomputers. Thus, the APAC National Facility is indispensable for our research.


Principal Investigator

Shin-Ho Chung
Chemistry
Faculty of Science
ANU

Project

r06, x26, w16, w50, d32

Facilities Used

VPP, SC, PC, MDSS

Co-Investigators

Turgut Bastug
Ben Corry
Matthew Hoyles
Taira Vora
Chemistry
Faculty of Science
ANU

Serdar Kuyucak
Megan O'Mara
Theoretical Physics
RSPhysSE
ANU

Roger Brown
ANU Supercomputer Facility
ANU

David Saint
Department of Physiology
University of Adelaide

Toby Allen
Biochemistry / Physiology and Biophysics
Weill Medical College of Cornell University
New York, USA

RFCD Codes

270104


Significant Achievements, Anticipated Outcomes and Future Work

The field of ion channels has entered into a rapid phase of development in the last few years, partly due to the breakthroughs in determination of the crystal structures of membrane proteins and advances in computer simulations of biomolecules. These advances have finally enabled the long-dreamed goal of relating function of a channel to its underlying atomic structure through the fundamental processes operating in electrolyte solutions. Using the newly unravelled structural information, we have succeeded in elucidating the mechanisms underlying the permeation of ions across the potassium channel, and explaining how the channel allows potassium ions to move across, while rejecting sodium ions. The experimentally-determined structure of the potassium channel is one of many different types found in nature, which differ widely in their conductances and gating characteristics. We employed molecular dynamics calculations and Brownian dynamics simulations to demonstrate that the widely differing properties of potassium channels found in nature can be understood by small modifications of the channel geometry.

On the basis of known experimental properties of other channels, whose crystal structures are not yet determined, and insights gathered from our studies on the potassium channel, we are planning to build their models and deduce some of the salient structural properties. Among the channels we wish to study are the L-type calcium channel, which is necessary for neurotransmission, muscle contraction and neurochemical modulation, the sodium channel, the activation of which generates nerve impulses, and the glycine channel, which by allowing chloride ions to move inside of the cell reduces neuronal excitability. We anticipate that each of the channel models we deduce using the computational methods will closely reproduce its experimental properties and capture some of the salient structural features of the channel protein.

 

Computational Techniques Used

The main computational tools that we make use of in our studies are molecular dynamics calculations and stochastic dynamics simulations. Of the several tools in statistical mechanics that treat the dynamics of nonequilibrium systems, Brownian dynamics (which we use) is the most widely known. The algorithm and code for Brownian dynamics were developed and gradually refined by our group over the past 5 years. In Brownian dynamics simulations, the Langevin equation is solved repeatedly to trace the trajectory of every ion in the assembly. Snapshots of the simulation system are taken at short time intervals for many millions of timesteps. At each time, the Langevin equation is integrated to obtain the velocity of each ion to determine to which position the ion will move in the next timestep. The new coordinates of all ions in the assembly are deduced, and the calculation is repeated. By repeating this process for a sufficiently long period of time, we can deduce how many ions move across the channel in a fixed period of simulation time. Without the computational power provided by the APAC National Facility, we would not have been able to carry out any of our studies.

For molecular dynamics calculations, we make use of two commercial packages - CHARMM and GROMAC. These packages enable us to follow the trajectories of N particles interacting via a many-body potential using Newton's equation of motion. The trajectory data so generated are stored at certain intervals, which are analyzed subsequently to determine the structural and dynamical properties of a system. Quantities such as free energy, mean square displacement, radial distribution function and other correlations functions are calculated from an ensemble average of several simulations.

 

Publications, Awards and External Funding

External Funding

NHMRC (2000-2004) - Approx. $1,000,000
ARC Discovery (2002-2004) - Approx. $220,000
APAC (2002) - Approx. $70,000

Publications

B. Corry, S. Kuyucak, S.H. Chung, Test of Poisson-Nernst-Planck Theory in Ion Channels, Journal of General Physiology, 114, 1999, 597-599.

T.W. Allen, M. Hoyles, S. Kuyucak, S.H. Chung, Molecular and Brownian Dynamics Study of Ion Selectivity and Conductivity in the potassium Channel, Chemical Physics Letters, 313, 1999, 358-365.

T.W. Allen, S. Kuyucak, S.H. Chung, Molecular Dynamics Study of the KcsA Potassium Channel, Biophysical Journal 77, 1999, 2502-2516.

S.H. Chung, T.W. Allen, M. Hoyles, S. Kuyucak, Permeation of Ions across the Potassium Channel: Brownian Dynamics Studies, Biophysical Journal 77, 1999, 2517-2533.

T.W. Allen, S. Kuyucak, S.H. Chung, The Effect of Hydrophobic and Hydrophilic Channel Walls on the Structure and Diffusion of Water and Ions, Journal of Chemical Physics, 111, 1999, 7985-7999.

D. Saint, S. H. Chung, Variability of Channel Subconductance States of the Cardiac Sodium Channel Induced by Protease, Receptors and Channels, 6, 1999, 283-294.

D. S. Poskitt, K. Dogancay, S. H. Chung, A New Analytical Method of Studying Post-Synaptic Currents in the Brain, Mathematical Biosciences, 161, 1999, 15-41, 1999.

D. Poskitt, K. Dogancay, S. H. Chung, Double Bblind Deconvolution: the Analysis of Post-Synaptic Currents in Nerve Cells, Journal of the Royal Statistical Society, B61, 1999, 191-212.

B. Corry, S. Kuyucak, S. H. Chung, Invalidity of Continuum Theories of Electrolytes in Nanopores. Chemical Physics Letters, 320, 2000, 35-41.

G. Moy, B. Corry, S. Kuyucak, S. H. Chung, Tests of Continuum Theories as Models of Ion Channels: I. Poisson-Boltzmann Theory Versus Brownian Dynamics. Biophysical Journal, 78, 2000, 2349-2363.

B. Corry, S. Kuyucak, S. H. Chung, Tests of Continuum Theories as Models of Ion Channels: II. Poisson-Nernst-Planck Theory Versus Brownian Dynamics, Biophysical Journal, 78, 2000, 2364-2381.

T. Allen, S. Kuyucak, S. H. Chung, Molecular Dynamics Estimates of Ion Diffusion in Model Hydrophobic and the KcsA Potassium Channels. Biophysical Chemistry, 86, 2000, 1-14.

T. Allen, A. Bliznyuk, A. P. Rendell, S. Kuyucak, S. H. Chung, The Potassium Channel: Structure, Selectivity and Diffusion, Journal of Chemical Physics, 112, 2000, 8191-8204.

B. Corry, T. W. Allen, S. Kuyucak, S. H. Chung, A Model of Calcium Channels, Biochimica et Biophysica Acta - Biomembranes, 1509, 2000, 1-6.

S. H. Chung, S. Kuyucak, Predicting Channel Function from Channel Structure Using Brownian Dynamics Simulations, Clinical & Experimental Pharmacology & Physiology, 28, 2001, 89-94.

B. Corry, T. W. Allen, S. Kuyucak, S. H. Chung, Mechanisms of Permeation and Selectivity in Calcium Channels, Biophysical Journal, 80, 2001, 195-214.

T. Allen, S. H. Chung, Brownian Dynamics Study of an Open-State KcsA Potassium Channel, Biochimica et Biophysica Acta - Biomembranes 1515, 2001, 83-91, 2001.

S. H. Chung, T. W. Allen, S. Kuyucak. Conducting-State Properties of the KcsA Potassium Channel from Molecular and Brownian Dynamics Simulations, Biophysical Journal, 82, 2002,628-645.

S. Kuyucak, O. S. Andersen, S. H. Chung, Models of Permeation in Ion Channels, Reports on Progress in Physics 64, 2001, 1427-1472.

A. A. Blinznyuk, A. P. Rendell, T. W. Allen, S. H. Chung, The Potassium Channel: Comparison of Linear Scaling Semiempirical and Molecular Mechanics Representations of the Electrostatic Potention, Journal of Physical Chemistry, 2001, in press.

S. Kuyucak, S. H. Chung, Permeation Models and Structure-Function Relationships in Ion Channels, Journal of Biological Physics, 2001, in press.

S. H. Chung, T. W. Allen, S. Kuyucak, Modeling Diverse Range of Potassium Channels with Brownian Dynamics, Biophysical Journal, 2002, in press.

B. Corry, M. Hoyles, T. Allen, M. Walker, S. Kuyucak, S. H. Chung, Reservoir Boundaries in Brownian Dynamics Simulations of Ion Channels, Biophysicl Journal, 2002, in press.

S. H. Chung, S. Kuyucak, Ion Channels: Recent Progress and Prospects, European Biophysics Journal, 2002, in press.

S. H. Chung, S. Kuyucak, Recent Advances in Ion Channel Research, Biochimica et Biophysica Acta - Biomembranes, 2002, in press.