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Chapter 8 : From Prokaryotes to Eukaryotes: Molecular Modeling and Simulation Studies of Ion Channels

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Abstract:

This chapter focuses on homology modeling and molecular dynamics (MD) simulations studies of ion channels for the range of single cell organisms from prokaryotes to eukaryotes. The glutamate receptor channels (GluRs) share some distant homology in their transmembrane (TM) domains with K channels but possess distinct extracellular ligand-binding domains for which several structures, of both bacterial and mammalian homologs, are known. It can be seen that molecular modeling and simulations can contribute to studies of ion channels in two respects. Modeling studies enable extrapolation from experimental structures of prokaryotic ion channels to molecular models of eukaryotic homologs, thus aiding design and interpretation of, for example, mutation experiments for dissecting structure-function relationships. Ion channel structures and ion channel models may also be used as the basis of multinanosecond MD simulations. Finally, it will become increasingly important to run multiple simulations on multiple channels to allow comparative analysis of simulation results, which in turn will enable the formulation of more general hypotheses concerning the relationship between the conformational dynamics of channel proteins and their physiological functions.

Citation: Biggin P, Grottesi A, Sansom M. 2005. From Prokaryotes to Eukaryotes: Molecular Modeling and Simulation Studies of Ion Channels, p 133-152. In Kubalski A, Martinac B (ed), Bacterial Ion Channels and Their Eukaryotic Homologs. ASM Press, Washington, DC. doi: 10.1128/9781555816452.ch8

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Integral Membrane Proteins
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Ion Channels
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Figures

Image of Figure 1.
Figure 1.

Schematic diagram of the role of modeling and simulation in studying the structure and function of ion channels. Protein crystallography (PX) yields structures of bacterial channels and their constituent domain/subunits. Molecular modeling may be used to integrate these structures within a complete model of a mammalian ion channel. The latter model may then be used as the starting point for simulation studies of channel structure-function relationships.

Citation: Biggin P, Grottesi A, Sansom M. 2005. From Prokaryotes to Eukaryotes: Molecular Modeling and Simulation Studies of Ion Channels, p 133-152. In Kubalski A, Martinac B (ed), Bacterial Ion Channels and Their Eukaryotic Homologs. ASM Press, Washington, DC. doi: 10.1128/9781555816452.ch8
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Image of Figure 2.
Figure 2.

Sequence alignment of the core TM pore domain of K channels and GluRs. The locations of the slide helix (in Kir channels), the M1/S5 helix, the P helix and filter, and the M2/S6 helix are indicated.

Citation: Biggin P, Grottesi A, Sansom M. 2005. From Prokaryotes to Eukaryotes: Molecular Modeling and Simulation Studies of Ion Channels, p 133-152. In Kubalski A, Martinac B (ed), Bacterial Ion Channels and Their Eukaryotic Homologs. ASM Press, Washington, DC. doi: 10.1128/9781555816452.ch8
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Image of Figure 3.
Figure 3.

(A) Closed and open conformations of a K channel pore domain as revealed by the X-ray structures of KcsA and MthK, respectively. In both cases, only the structure of the TM domain is shown. The vertical ellipse indicates the location of the selectivity filter in the KcsA structure. The approximate location of the lipid bilayer is indicated by the horizontal gray broken lines. (B) Structure of the filter region of KcsA (for clarity only two of the four polypeptide chains are shown). The locations of the possible binding sites (Sto S4) for the potassium ions are shown as spheres.

Citation: Biggin P, Grottesi A, Sansom M. 2005. From Prokaryotes to Eukaryotes: Molecular Modeling and Simulation Studies of Ion Channels, p 133-152. In Kubalski A, Martinac B (ed), Bacterial Ion Channels and Their Eukaryotic Homologs. ASM Press, Washington, DC. doi: 10.1128/9781555816452.ch8
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Image of Figure 4.
Figure 4.

K channel simulation systems illustrated using KirBac. For clarity only two subunits of the protein are shown, and all water molecules and ions are omitted. KirBac is shown embedded in a membrane-mimetic octane slab (A) and a 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) lipid bilayer (B). In the latter diagram, the helices are labeled and the phosphorus atoms of the lipid molecules are shown as gray spheres.

Citation: Biggin P, Grottesi A, Sansom M. 2005. From Prokaryotes to Eukaryotes: Molecular Modeling and Simulation Studies of Ion Channels, p 133-152. In Kubalski A, Martinac B (ed), Bacterial Ion Channels and Their Eukaryotic Homologs. ASM Press, Washington, DC. doi: 10.1128/9781555816452.ch8
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Image of Figure 5.
Figure 5.

Structures of the selectivity filter in crystal structures (PX) and simulations (MD) are compared. In each case the backbones of two subunits of the filter are shown. The PX structures are of KcsA, crystallized in the presence of a high concentration of K ions (PDB code 1k4c) and in the presence of a low concentration of Kions (PDB code 1k4d). The MD structures are of KcsA, from a simulation in which all Kions have left the filter ( ), and of Kir-Bac at the end (10 ns) of a simulation in the absence of Kions ( ).

Citation: Biggin P, Grottesi A, Sansom M. 2005. From Prokaryotes to Eukaryotes: Molecular Modeling and Simulation Studies of Ion Channels, p 133-152. In Kubalski A, Martinac B (ed), Bacterial Ion Channels and Their Eukaryotic Homologs. ASM Press, Washington, DC. doi: 10.1128/9781555816452.ch8
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Image of Figure 6.
Figure 6.

Kinking of the pore-lining M2 or S6 helix of K channels associated with channel activation. PX compares the M2 helices from the crystal structures of Kir-Bac (closed) and MthK (open) with the S6 helix from KvAP. MD, KirBac shows selected structures of M2 helices from a simulation of KirBac ( ). MD, Kv-S6 shows a selected structure of the S6 helix from a simulation of a model of the pore domain of the Shaker Kv channel ( ).

Citation: Biggin P, Grottesi A, Sansom M. 2005. From Prokaryotes to Eukaryotes: Molecular Modeling and Simulation Studies of Ion Channels, p 133-152. In Kubalski A, Martinac B (ed), Bacterial Ion Channels and Their Eukaryotic Homologs. ASM Press, Washington, DC. doi: 10.1128/9781555816452.ch8
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