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Stability, permeation and blocking properties of K+ channels

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Potassium channels are a large sub-family of ionic channels, which have the capability of selecting K+ over other monovalent cations (like Na+). Using classical molecular dynamics and density functional theory calculations we are investigating the properties of permeation, selectivity and blocking of the KcsA potassium channel.
Classical MD turned out to be a powerful tool for studying the microscopic permeation events occurring during ion flux, since these events have a time scale comparable with the one accessible by simulations.
Using MD results and sequence homology, we were able to understand the relevance of conserved residues in the protein stability and fundamental aspects of potassium permeation and selectivity [5,6]. The docking of a small organic channel blocker (TEA+) was also investigated [7], providing rationalization of the ligand-channel molecular interactions studied by previous experiments [R. MacKinnon, G. Yellen, Science 1990, 250 276-279]. The proposed blocking mechanisms has been later confirmed by experimental structural data [Lenaeus et al. Nat. Str. Biol. 5, 454 (2005)]. The ionic transport was further studied by quantum mechanical methods, revealing the electronic structure changes of the protein during an elementary step of the ion permeation [9]. The relevance of the electronic structure on the modelling the ionic permeation has been further studied by means of QM/MM scheme [21,23]. The potential energy surface of complex systems (such as ions permeating an ionic channel) can be investigated using non-equilibrium Molecular Dynamics techniques. These methods allow us to obtain equilibrium thermodynamics properties of a system using a properly weighted set of non-equilibrium systems. The practical application of such technique to water exchange at alkali ions [12] provides encouraging results for the application of this method to ion flux through channels.
The KcsA K+ channel. (A) Classical MD simulation [5,6]. (B) Detail of the modelled interaction between the organic channel blocker TEA+ and four tyrosine residues on the channel surface [7]. (C). Polarization of the protein ligand carbonyls by K+ [9]. The light blue contour represents the electronic density displacement upon ion binding.

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