LANS Informal Seminar: Bob Eisenberg

Seminar Title: Self-organized selectivity in Calcium and Sodium Channels: Biomimetic Designs now ready for Serious Computation
Speaker: Bob Eisenberg, Bard Professor and Chairman Dept of Molecular Biophysics & Physiology, Rush Medical Center

Date/Time: 2009-09-23 15:00
Location: TBA

Description:
Ion channels are irresistible objects for biological study because they are the [nano] ‘valves of life’ controlling an enormous range of biological function, much as transistors control computers. Ion channels are much easier to simulate than many proteins because conformation changes are not involved in channel function, once the channel is open. 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. Macroscopic electric fields and concentration gradients produce substantial flows which are the natural biological function of the channel, making equilibrium analysis unhelpful. Multiscale issues are nontrivial: simulations must deal with concentrations of 10^(−7) to 55 M of different chemical species. Ion transit takes ~ 10^(−8) sec compared to a calculation time step of 10^(−16) sec and a biological time scale of 10^(−4) — 1 sec.

Computations in full three dimensions are not yet feasible. In reduced dimensionality, however, a simple physical model does surprisingly well. One model with the same two parameters accounts for qualitatively different selectivity of both calcium and sodium channels in a wide range conditions. The model does not involve any traditional chemical binding energies at all. 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 indeed, but as an output of the model, not as an input. The relationship of ions and side chains vary with ionic solution and are different in different channels and solutions. 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 self-organized and at their free energy minimum, forming different structures in different conditions. A variational approach is immediately suggested by these results and one is well under way, applying the methods of Chun Liu (Associate Director, IMA Minnesota) and colleagues, perfected in electro-rheology.

Practical exploitation to design selective biomimetic membranes for desalination and detoxification depends on computation. Trial and error methods are not likely to be efficient enough to allow practical design. Computational success depends on the accurate (± 3%) estimation of both energy and entropy of the self-organized structure in three dimensions of space and one of time.

Computational design of these biomimetric systems is an unmet challenge that can soon be met because of the memory bandwidth and size of next generation computers.