We apply engineering as usual to biological ion channels to determine which physics are used by the channels to achieve crucial biological functions. For instance, how do channels select among physiological ions, and how do they conduct the selected ions through cell membranes? How do channels regulate their ionic conduction in response to the cell's membrane potential? These capabilities underly bioelectricity.

Much of our current work is computational, with some experimental extensions to test the theories we develop. We collaborate closely with many scientists in diverse disciplines in the U.S and abroad. These include researchers in physical chemistry, computational electronics, and applied mathematics, who work with us to apply advanced methods of their fields to our biological problem. Our results are published in physical as well as physiological journals (see below).

 

 

Like engineers, we try to focus on elements that are crucial for a function and to elaborate their physical interactions to the level of detail needed to understand and predict the function. This reductionist approach is illustrated in a our view of the `selectivity filter' of an L-type Ca channel (see figure). Here, some crucial charged atoms of the channel lining are represented explicitly (red spheres). Their interactions with permeating ions (green and yellow spheres) are computed explicitly. The rest of the channel macromolecule is described at a much coarser scale of resolution. We sample the interactions of interest using direct (Monte-Carlo) simulation of this charged particle system, and we seek to develop statistical-mechanical theory describing the system's average behavior (such as the average number of Ca ions attracted into the selectivity filter from baths of varied ionic compositions). Equilibrium theory that we work out for this filter is included into a drift/diffusion description of ion flow that occurs when ions experience a driving force across the channel.

 

From Right to Left:
Alex Peyser, Umbrella Tree, Wolfgang Nonner

 

1. Boda D, Valiskó M, Henderson D, Eisenberg B, Gillespie D, Nonner W. Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion. J Gen Physiol. 2009 May;133(5):497-509.
2. Nie L, Zhu J, Gratton MA, Liao A, Mu KJ, Nonner W, Richardson GP, Yamoah EN. Molecular identity and functional properties of a novel T-type Ca2+ channel cloned from the sensory epithelia of the mouse inner ear. J Neurophysiol. 2008 Oct;100(4):2287-99. Epub 2008 Aug 27. article
3. Roth R, Gillespie D, Nonner W, Eisenberg RE. Bubbles, gating, and anesthetics in ion channels. Biophys J. 2008 Jun;94(11):4282-98. Epub 2008 Jan 30.
4. Boda D, Nonner W, Henderson D, Eisenberg B, Gillespie D. Volume exclusion in calcium selective channels. Biophys J. 2008 May 1;94(9):3486-96. Epub 2008 Jan 16.
5. Boda D, Nonner W, Valiskó M, Henderson D, Eisenberg B, Gillespie D. Steric selectivity in Na channels arising from protein polarization and mobile side chains. Biophys J. 2007 Sep 15;93(6):1960-80. Epub 2007 May 25.
6. Boda D, Valiskó M, Eisenberg B, Nonner W, Henderson D, Gillespie D. Combined effect of pore radius and protein dielectric coefficient on the selectivity of a calcium channel. Phys Rev Lett. 2007 Apr 20;98(16):168102. Epub 2007 Apr 17.
7. Miedema H, Vrouenraets M, Wierenga J, Gillespie D, Eisenberg B, Meijberg W, Nonner W. Ca2+ selectivity of a chemically modified OmpF with reduced pore volume. Biophys J. 2006 Dec 15;91(12):4392-400. Epub 2006 Sep 22.
8. Boda D, Valiskó M, Eisenberg B, Nonner W, Henderson D, Gillespie D. The effect of protein dielectric coefficient on the ionic selectivity of a calcium channel. J Chem Phys. 2006 Jul 21;125(3):34901.
9. Nonner W, Peyser A, Gillespie D, Eisenberg B (2004) Relating microscopic charge movement to macroscopic currents: the Ramo-Shockley theorem applied to ion channels. Biophys J. 87(6):3716-22.
10. Miedema H, Meter-Arkema A, Wierenga J, Tang J, Eisenberg B, Nonner W, Hektor H, Gillespie D, Meijberg W (2004) Permeation properties of an engineered bacterial OmpF porin containing the EEEE-locus of Ca2+ channels. Biophys J. 87(5):3137-47.
11. Boda D, Gillespie D, Nonner W, Henderson D, Eisenberg B (2004) Computing induced charges in inhomogeneous dielectric media: application in a Monte Carlo simulation of complex ionic systems. Phys Rev E Stat Nonlin Soft Matter Phys. 69(4 Pt 2):046702.
12. Gardner CL, Nonner W, and Eisenberg B (2004). Electrodiffusion model simulation in ionic channels: 1D simulations. J. Computational Electronics 3(1):25-31.
13. Gillespie D, Nonner W, and Eisenberg B (2002). Coupling Poisson-Nernst-Planck and density functional theory to calculate ion flux. J. Physics.: Condensed Matter 14:12129-12145.
14. Nonner W, Catacuzzeno L, Eisenberg B (2000) Binding and selectivity in L-type calcium channels: a mean spherical approximation. Biophys J. 79(4):1976-92.
15. Nonner W. and Eisenberg B (1998). Ion permeation and glutamate residues linked by Poisson-Nernst-Planck theory in L-type calcium channels. Biophys. J. 75:1287-1305.
16. Conti F, Hille B, Neumcke B, Nonner W, and Staempfli R (1976). Measurement of the conductance of the sodium channel from current fluctuations at the node of Ranvier. J. Physiol. 262:699-727.
17. Nonner W, Rojas E, and Staempfli R (1975). Gating currents in the node of Ranvier: voltage and time dependence. Phil. Trans. R. Soc. Lond. B. 270:483-492.