Max Planck Institute for Dynamics and Self-Organization -- Department for Nonlinear Dynamics and Network Dynamics Group
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BCCN AG-Seminar

Tuesday, 10.11.2009 16 c.t.

Self-organized Selectivity in Calcium and Sodium Channels

by Prof. Dr. Robert S. Eisenberg
from Department of Molecular Biophysics & Physiology, Rush University Medical Center, Chicago, IL, USA

Contact person: Fred Wolf

Location

Seminarraum Haus 2, 4. Stock (Bunsenstr.)

Abstract

Ion channels are appealing objects for physical investigation because conformation changes are not involved in channel function, once the channel is open. Ions move in a structure that does not vary even by 0.1 Å on the biological time scale of 10-5 sec. Open channels are interesting objects for chemical study because they effectively select among chemically similar ions, under unfavorable circumstances. Channels are interesting objects for physical study because they contain an enormous density of charge, fixed, mobile, and induced. Direct simulation of channel behavior in atomic detail is difficult if not impossible, because ion transit takes ~ 10 nsec; concentrations of 10-6 to 55 M must be accurately represented in a single calculation, and macroscopic electric fields and concentration gradients produce substantial flows, making equilibrium analysis unhelpful. Simple models are surprisingly successful in describing selectivity. The dramatic selectivity of Ca channels arises automatically if the ions and glutamic oxygens of the selectivity filter of the channel are represented as charged spheres within a dielectric sheath. The four permanent charges EEEE of the selectivity filter force the channel to hold four positive mobile charges, making a concentration of ~ 17M univalent charge. Four (monovalent) sodium ions occupy twice the volume of two (divalent) calciums; the resulting difference in crowding produces calcium selectivity, by changing ion specific free energy. Amazingly, the same model with the same parameters produces a highly selective Na+ channel if the selectivity filter is mutated to DEKA. The resulting Na channel is both charge selective for Na+ vs. Ca++ and size selective for Na+ vs. K+. This model accounts for selectivity in a wide range conditions with two parameters with the same unchanging values in both calcium and sodium channels. The model does not involve any traditional chemical energies. The binding free energy is an output of the calculation, produced by the crowding of charged spheres in a very small space. How can such a simple model give such specific results when crystallographic wisdom and chemical intuition says that selectivity depends on the precise structural relation of ions and side chains? The answer is that structure is the computed consequence of the forces in this model and is very important, but as an output of the model, not as an input. The relationship of ions and side chains vary with ionic solution and are very different in simulations of Na and Ca channels at different concentrations. Selectivity is a consequence of the ‘induced fit’ of side chains to ions and vice versa. The simplified model (probably) works because the structures in both the model and the real channel are the most stable. They are self-organized and at their free energy minimum, forming different structures in different conditions. It seems that an important biological function can be understood by an oversimplified model if the model calculates the ‘most stable’ structure as it changes from solution to solution, and mutation to mutation. Calculations of ‘free energy of binding’ in infinitely dilute or ideal solutions are not likely to give useful estimates of binding in physiological solutions.

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