Ion selectivity of alpha-hemolysin with beta-cyclodextrin adapter. II. Multi-ion effects studied with grand canonical Monte Carlo/Brownian dynamics simulations.

In a previous study of ion selectivity of alpha-hemolysin (alphaHL) in complex with beta-cyclodextrin (betaCD) adapter, we calculated the potential of mean force (PMF) and characterized the self-diffusion coefficients of isolated K(+) and Cl(-) ions using molecular dynamics simulations (Y. Luo et al., "Ion Selectivity of alpha-Hemolysin with beta-Cyclodextrin Adapter: I. Single Ion Potential of Mean Force and Diffusion Coefficient"). In the present effort, these results pertaining to single isolated ions in the wide aqueous pore are extended to take into account multi-ion effects. The grand canonical Monte Carlo/Brownian dynamics (GCMC/BD) algorithm is used to simulate ion currents through the wild-type alphaHL ion channel, as well as two engineered alphaHL mutants, with and without the cyclic oligosaccaride betaCD lodged in the lumen of the pore. The GCMC/BD current-voltage curves agree well with experimental results and show that betaCD increases the anion selectivity of alphaHL. Comparisons between multi-ion PMFs from GCMC/BD simulations and single-ion PMFs demonstrate that multi-ion effects and pore shape are crucial for explaining this behavior. It is concluded that the narrow betaCD adapter increases the anion selectivity of alphaHL because it reduces 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 alphaHL side chains.