Ion Selectivity of α-Hemolysin with a β-Cyclodextrin Adapter. I. Single Ion Potential of Mean Force and Diffusion Coefficient

The alpha-hemolysin (alpha HL) is a self-assembling exotoxin that binds to the membrane of a susceptible host cell and causes its death. Experimental Studies show that electrically neutral beta-cyclodextrin (beta CD) can insert into the alpha HL channel and significantly increase its anion selectivity. To understand how beta CD can affect ion selectivity, molecular dynamics simulations and potential of mean force (PMF) calculations are carried out for different alpha HL channels with and without the beta CD adapter. A multiscale approach based on the generalized solvent boundary potential is used to reduce the size of the simulated system. The PMF profiles reveal that beta CD has no anion selectivity by itself but Can increase the Cl- selectivity of the alpha HL channel when lodged into the pore lumen. Analysis shows that beta CD causes a partial desolvation of ions and affects the orientation of nearby charged residues. The ion selectivity appears to result from increased electrostatic interaction between the ion and the channel due to a reduction in dielectric shielding by the solvent. These observations suggest a reasonable explanation of the ion selectivity and provide important information for further ion channel modification.