Theoretische Studien der Ionenpermeation in Kaliumkanälen

• Applicant: Dr. Bernhard Egwolf
• Subject Area: Experimental Condensed Matter Physics
• Term: from 2006 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 24839148

• Final Report Year: 2009

Final Report Abstract

In order to allow an efficient and accurate computation of currents through ion channels, a new reaction field method was developed and implemented into the grand canonical Monte Carlo/Brownian dynamics (GCMC/BD) program. The development of this method was inspired by the generalized Born method and, in addition, lead to an improved method for calculating generalized Born radii beyond the commonly used Coulomb approximation. GCMC/BD simulations of ion currents through wild type α-hemolysin (αHL) as well as two engineered αHL mutants, with and without the cyclic oligosaccaride β-cyclodextrin (β CD) lodged in the lumen of the pore, yielded new insights on the selectivity of this wide channel. It was found that the neutral β CD molecule is able to increase the anion selectivity of αHL by reducing the pore radius locally, which decreases the ionic screening and the dielectric shielding of the strong electrostatic field induced by a nearby ring of positively charged αHL side chains. In order to perform GCMC/BD simulations of potassium channels, an appropriate model for the narrow selectivity filter of these channels was constructed. This made it possible to simulate potassium currents through new open state KcsA crystal structures varying in the width of the channel opening as well as an open state Kv1.2 structure. Extensive 3-dimensinal all-atom umbrella sampling simulations were performed to study the dynamic processes of sodium and potassium entering the selectivity filter of KcsA. The resulting potentials of mean force show that sodium is repelled between the binding sites S1 and S2 of the selectivity filter, whereas potassium can pass.

Publications

• A New Reaction Field Method for Brownian Dynamics Simulations of Ion Channel Permeation. Biophys. J. Supp. Abs. 94, 745a-746a, 2008
  B. Egwolf and B. Roux
  
• Multi-Ion Energetics in Inward Rectifier Potassium Channels. Biophys. J. Supp. Abs. 94, 718a, 2008
  J. L. Robertson, B. Egwolf, L.G. Palmer, and B. Roux
  
• Computational Study on the Ion Selectivity of Modified Alpha-Hemolysin Channels. Biophys. J. Supp. Abs. 96, 662a, 2009
  B. Egwolf, Y. Luo, D. E. Walters, and B. Roux