Biological ion channels are responsible for, and regulate the
communication system in the body. In this thesis I develop, test and
apply theoretical models of ion channels, that can relate their
structure to their functional properties. Brownian dynamics
simulations are introduced, in which the motions of individual ions
are simulated as they move through the channel and in baths attached
to each end. The techniques for setting boundary conditions which
maintain ion concentrations in the baths and provide a driving
potential are tested. Provided the bath size is large enough, all
boundary conditions studied yield the same results.
¶
Continuum theories of electrolytes have previously been used to study
ion permeation. However, I show that these continuum models do not
accurately reproduce the physics taking place inside ion channels by
directly comparing the results of both equilibrium Poisson-Boltzmann
theory, and non-equilibrium Poisson-Nernst-Planck theory to
simulations. In both cases spurious shielding effects are found to
cancel out forces that play an important role in ion permeation. In
particular, the `reaction field' created by the ion entering the
narrow channel is underestimated. Attempts to correct these problems
by adding extra force terms to account for this reaction field also
fail.
¶
A model of the L-type calcium channel is presented and studied using
Brownian dynamics simulations and electrostatic calculations. The
mechanisms of permeation and selectivity are explained as the result
of simple electrostatic interactions between ions and the fixed
charges in the protein. The complex conductance properties of the
channel, including the current-voltage and current-concentration
relationships, the anomalous mole fraction behaviour between sodium
and calcium ions, the attenuation of calcium currents by monovalent
ions and the effects of mutating glutamate residues, are all
reproduced.
¶
Finally, the simulation and electrostatic calculation methods are used
to study the gramicidin A channel. It is found that the continuum
electrostatic calculations break down in this narrow channel, as the
concept of applying a uniform dielectric constant is not accurate in
this situation. Thus, the permeation properties of the channel are
examined using Brownian dynamics simulations without electrostatic
calculations. Future applications and improvements of the Brownian
dynamics simulation technique are also described.
| Identifer | oai:union.ndltd.org:ADTP/216739 |
| Date | January 2003 |
| Creators | Corry, Ben Alexander, ben.corry@anu.edu.au |
| Publisher | The Australian National University. Research School of Physical Sciences and Engineering |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://www.anu.edu.au/legal/copyright/copyrit.html), Copyright Ben Alexander Corry |
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