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Ion Channels

Molecular Dynamics Simulation of Low Molecular Weight Ion Channels

Transmembrane proteins form typically 30% of a genome, and amongst this group Ion Channels play numerous key biological roles such as in nerve conduction, response to toxins, disease infection, etc.

A key element in a typical ion channel is a bundle of alpha helices transverse to the lipid bilayer. The helix bundle external surface consists of hydrophobic groups, compatible with the external lipid environment, while the internal pore of the helix bundle supports a water column. Ion penetration through the ion channel is through this water column, which enables conservation of the ion's hydration shell in the transport process.

We have implemented Molecular Dynamics (MD) Simulations of relatively low molecular weight functional channels, typically helix tetramer transmembrane sequences. This has enabled us to supply answers to several questions of biological importance for which no direct experimental answer is available. A key issue is the structure of the channel/water/lipid complex. X-ray structures for ion channels are rarely available, because of their difficulty in crystallization, and MD can supply such information given basic input such as the number of helices in the bundle. A second issue is the nature of the gating process, whereby the channel is opened/closed by an external stimulus, e.g. a voltage or the concentration of an ion such as H+ . We implemented simulations over several nanoseconds including both water and lipid phases, totalling of order 10,000 atoms. A simulation took typically several months on an SP2 system. We were unable to explore the more extended time domain required for passage of an ion through a channel.

Figure 1. LS2 Proton Channel

We have studied [1] two classes of ion channels. The first [5,6] is a group of functional synthetic ion channels termed LS2 and LS3. For example the LS2 channel (Fig. 1) consists of a tetramer of the peptide sequence Ac-(LSLLLSL)3 -CONH 2 , where L=Leucine, a hydrophobic residue, and S=Serine, which contains a hydrophilic OH group. The simulation [6] confirms the architectural principles of the experimentalists, that the hydrophilic groups are oriented towards the pore (OH groups denoted in green in Fig. 1), which becomes highly hydrated with 29 waters (only helix atoms shown in figure).

The M2 proton channel of the Influenza A virus plays a crucial role in infection. Its blocking by a group of drugs including adamantylidine and relatives comprises a treatment for the disease. The channel is a tetramer and is gated by pH, being conducting only below a threshold pH = 5.8. The gating is known to be associated in some manner with protonation of the His residue, of which there is one per helix.Our interest from the point of view of MD [1,3,4] lay in understanding the structure and gating of the channel.

The results for simulation of an unprotonated M2 channel [4] are illustrated in Fig. 2 left. It is seen that the water column (only protein and channel water are illustrated) is broken by bulky ring molecules, which are in fact the histidines supplemented by tryptophans, as also occurred for single protonation. When double protonation was investigated however [3], the channelopened up (right, Fig. 2), giving the open state with 45 channel waters. In fact recent experimental work supports double protonation as the ionization state of the open state of the channel [2].

Figure 2: M2 Proton Channel of Influenza A Virus

Molecular Dynamics Study of Structure and Gating of Low Molecular Weight Ion Channels', D.M. Newns, Q. Zhong, P.B. Moore, T. Husslein, P.C. Pattnaik, and M.L. Klein, Comp. Chem. (special issue on parallel Computing), in press.
W. F. DeGrado and J.D. Lear, private commun.
Two possible conducting states of the Influenza A virus M2 Ion Channel', Q. Zhong, D. M. Newns, P.C. Pattnaik, J.D. Lear, and M.L. Klein, FEBS letters, June (2000).
The M2 Channel of Influenza A virus: a molecular dynamics study' Q. Zhong, T. Husslein, P.B. Moore, D. M. Newns, P.C. Pattnaik, and M.L. Klein, FEBS Letters, 434, 265 (1998).
Molecular Dynamics simulation of the LS3 voltage-gated ion channel', Q. Zhong, P.B. Moore, D. M. Newns, and M.L. Klein, FEBS Letters, 427, 267 (1998).
Molecular Dynamics Simulation of a Synthetic Ion Channel', Q. Zhong, Q. Jiang, P.B. Moore, D. M. Newns, and M.L. Klein, Biophysics Journal, 74, 3 (1998).