Molecular Dynamics Studies of Membrane Ion Channels


Principal Investigator

Toby W. Allen

Department of Chemistry

The Faculties


w50 - VPP, PC

T o investigate the underlying physical mechanisms
that control the passage of ions through biological
ion channels, one must treat protein and solvent molecules explicitly during computer simulation. This is done with the molecular dynamics (MD) technique. Using continuum theories, including Poisson-Boltzmann, Nernst-Plank and Poisson-Nernst-Plank, and the semi- microscopic Brownian dynamics (BD) method, simplified models of ion channels have been studied in the past, with limited success. The major impediments to success have been the lack of detailed structural information and the need to assume values for significant physical properties such as the dielectric and ion diffusion constants. In MD simulations, there is no need to assume mean physical properties of ions and solvent, since all molecules are included in the dynamics simulations. However, the implementation of large numbers of protein and solvent molecules leads to very large system sizes. This factor, combined with the need for short time-steps so as to adequately describe short-range interactions, makes the MD technique computationally demanding. By simulating for a matter of nanoseconds, estimates of the energy barriers faced by ions traversing the channels, and estimates of ion diffusion coefficients have been found. These in turn can be implemented in BD simulations to study the channels over longer time periods so that conductance properties of the channels may be found. It is this combination of the microscopic and semi-microscopic approaches that will eventually lead to a thorough understanding of these important biological processes.

What are the results to date and the future of the work?

The recent determination of the structure of the potassium channel has permitted us to simulate a well defined system. Simulation has revealed equilibrated protein and water structure, self diffusion profiles, ion coordination, energy profiles and ion diffusion profiles. These findings have uncovered previously unknown mechanisms behind permeation and ion selectivity within this important ion channel. This combined with conductance properties found with concurrent BD simulations has produced a comprehensive theoretical survey of this family of channels.

- Appendix A



Future MD studies of this channel will involve the inclusion of more of the amino acid sequence so as to confirm our findings with a reduced segment of the experimentally determined protein. We also plan to make comparisons of electrostatic profiles with semi-empirical estimates, and undertake an extensive project examining the dielectric response of channel water and protein within the narrow selectivity filter region of the channel.

Our second major project has been the study of the effects of channel wall type (hydrophilic / hydrophobic) and size on diffusion. Long simulations of structured and smooth hydrophobic channels, and hydrophilic channels, have revealed the dependence of water and ion diffusion on channel size. This has been explained in terms of water structure (geometry, electrostatic interactions and dipole correlations). Large fluctuations in diffusion, especially self diffusion, with channel size have not before been seen. These variations have now been reported and explained. A new, computationally efficient, hydrophobic wall potential model has been thoroughly tested and shown to reproduce all channel water properties and ion diffusion across a wide range of channel sizes. The model we have developed is applicable to most biological ion channels as well as a variety of other pores. Use of the simplified cylindrical channels, with a computationally efficient wall constraint, provides an ideal avenue for investigations into dielectric response. The dielectric constant is a macroscopic quantity that is not well understood in narrow pore situations. The extensive MD simulations required to describe the dielectric response have begun and we hope to solve this fundamental problem in the near future.

What computational techniques are used?

All MD simulations are carried out with the CHARMM v25b2 package on the PC machine. The standard Verlet algorithm with bonds constrained by the SHAKE procedure is used. We use simple molecular models and make use of the most efficient list updating and cutoffs so as to improve computational efficiency.

BD simulations employ our findings from MD so as to produce channel conductances which compare to experiment. These are performed on the VPP with our own highly vectorized package. The BD algorithms have undergone considerable upgrades to improve vectorization and overall speed. This is the same program used by Dr S-H.Chung (Department of Chemistry) in his studies of permeation of ions through membrane channels.


S-H. Chung, T. W. Allen, M. Hoyles and S. Kuyucak, Molecular and Brownian dynamics study of ion permeation across the potassium channel. Submitted to Phys. Rev. Lett. November 1998.

T. W. Allen, S. Kuyucak and S-H. Chung, Molecular dynamics study of the potassium channel. Submitted to Biophys. J.

T. W. Allen, S. Kuyucak and S-H. Chung, A molecular dynamics study of the effects of pore size and structure on the diffusion of water and ions within model ion channels. In preparation.

Appendix A -


R S-H. Chung, M. Hoyles, T.W. Allen and S. Kuyucak, Study of ionic currents across a model membrane channel using Brownian dynamics. Biophys. J. 75. 793-809.
S-H. Chung, T. W. Allen, M. Hoyles and S. Kuyucak, 1999. Permeation of ions across the potassium channel: Brownian dynamics studies. Submitted to Biophys. J.
- Appendix A