Bias-Exchange Metadynamics Simulations: An Efficient Strategy for the Analysis of Conduction and Selectivity in Ion Channels

Domene C., Barbini P. & Furini. S, Journal of Chemical Theory and Computations, 2015

A common feature of the current strategies used to estimate the energy profiles of permeating ions is that the number and the kind of ions inside the channel need to be defined in advance. With bias-exchange metadynamics, this preliminary assumption is not necessary, and it is possible to analyse conduction events with different number of ions, and even different kind of ions, using the same set of simulations. Here we tested the method using a toy model of a Na+ channel. With this technique it was possible to explore conduction in a 4 dimensional space in less than 1 microsecond of simulation time, a fraction of the time needed with other approaches.




http://www.phys.rush.edu/BROWNIES/

Three-Dimensional Brownian Dynamics Simulator for the Study of Ion Permeation through Membrane Pores

Berti C. et al, Journal of Chemical Theory and Computations, 2014
A numerical simulator of brownian dynamics, for more information click of the BROWNIES logo... 





Na+ channels

Sodium selective channels are the major player in the raising phase of the action potential in excitable cells. In 2011 the first crystallographic structure of a Na+ selective channel was solved. This opened the way to theoretical studies about conduction and selectivity in this important class of membrane proteins.

https://sites.google.com/a/dbm.unisi.it/furini/research/ion-channels/figure_nav_correlation_energy_glu.png

Effects of the protonation state of the EEEE motif of a bacterial Na+-channel on conduction and pore structure

Furini S. & Domene C., Biophysical Journal, 2014

The filter of bacterial Na+ channel is characterised by a ring of 4 glutamate residues at its extracellular entrance. We analysed how the protonation states of these residues modify the conduction properties of the channel.





On Conduction in a Bacterial Sodium Channel

Furini S. & Domene C., Plos Comp Biol, 2012

Here we analyzed the conduction of Na+ and K+ ions through the selectivity filter of the NaVAb bacterial sodium channel. Differently from K+ channels, ion movements inside the filter appeared as weakly correlated. Permeation of Na+ ions experienced higher energy barriers compared to K+ ions, with possible implications for the selectivity mechanism.








NaK channel

The NaK channel is an interesting case study for understanding K+/Na+ selectivity. While the filter of NaK differs from the filter of K+ selective channels in a single aminoacid, the X-ray structure of NaK showed a water filled vestibule instead of the binding sites S1-S2 of K+ channels, and the permeabilities to K+ and Na+ are similar.



Nonselective Conduction in a Mutated NaK Channel with Three Cation-Binding Sites

Furini S. & Domene C., Biophysical Journal, 2012

Here we prove that a NaK channel mutated to mimic CNG channels and characterized by a filter with three K+ binding sites identical to sites S4-S2 of potassium channels has similar energy barriers for the conduction of K+ ions, Na+ ions and K+/Na+ ion mixtures. By comparison with similar energy calculations in K+ selective channels we propose a possible mechanism for ion selectivity.

 

Gating at the Selectivity Filter of Ion Channels that Conduct Na+ and K+ Ions

Furini S. & Domene C., Biophysical Journal, 2011

In this study we calculated the energy maps for conduction of sodium and potassium ions through wild-type NaK and several mutants. These energy profiles  suggest that the X-ray structure of NaK represents a non-conductive state. A possible conductive state of the NaK filter is proposed.



K+ channels

In 1998, the X-ray structure of the first K+ selective channel was solved. This represented a real turning point for the study of conduction and selectivity in ion channels.


Selectivity and permeation of alkali metal ions in K+-channels

Furini S. & Domene C., J Mol Biol, 2011

In this study we calculated the energy profiles for conduction of K+, Rb+, and mixtures of 3 K+ and 1 Na+ through the selectivity filter of the KirBac channel. K+ and Rb+ "see" the filter as a sequence of equally spaced binding sites, while the presence of a Na+ ion disrupts this chain. Our results support the hypothesis that selectivity is a property associated with to the multi-ion mechanism of conduction.


Atypical mechanism of conduction in potassium channels

Furini S. & Domene C., PNAS, 2009

Since the release of the first crystallographic structure of KcsA, it is widely accepted that K+ ions move through the channel in the configuration K+/water/K+/water. In this study we question this "dogma". Energetic analyses revealed that configurations with two K+ ions in adjacent binding sites are also possible, and that an alternative conduction mechanism with ions in adjacent sites or empty sites is also possible. Our hypothesis is that conduction through K+ channels is a much more chaotic process of what it is commonly believed.



Dynamics, energetics, and selectivity of the low-K+ KcsA channel structure

Domene C. & Furini S., J Mol Biol, 2009

The selectivity filter of KcsA was crystallized into two configurations, one open and one collapsed. Here, we analyzed how K+ ions bind to the collapsed structure of the filter.


Permeation of water through the KcsA K+ channel

Furini, S., Beckstein, O. & Domene, C., Proteins, 2009

Quite unexpectedly an extremely high water permeability was measured for the KcsA channel, higher than the permeability of some water channels. Here, we tried to identify the atomic details of these permeation events. According to our simulations the filter is not permeable by water, while a possible permeation pathway at the back of the filter was identified.




The Role of Conformation in Ion Permeation in a K+ Channel

Domene, C., Vemparala, S., Furini, S., Sharp, K. & Klein, M. L., J Am Chem Soc, 2008

Role of the Intracellular Cavity in Potassium Channel Conductivity

Furini, S., Zerbetto, F. & Cavalcanti, S. Journal of Physical Chemistry B, 2007

Application of the Poisson-Nernst-Planck Theory with Space-Dependent Diffusion Coefficients to KcsA

Furini, S., Zerbetto, F. & Cavalcanti, S. Biophys J, 2006

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