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

• Published in: The journal of physical chemistry. B 2010-01, Vol.114 (2), p.952-958
• Main Authors: Luo, Yun, Egwolf, Bernhard, Walters, D. Eric, Roux, Benoît
• Format: Article
• Language: English
• Subjects: B: Biophysical Chemistry; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Toxins - chemistry; Bacterial Toxins - genetics; beta-Cyclodextrins - chemistry; Crystallography, X-Ray; Diffusion; Hemolysin Proteins - chemistry; Hemolysin Proteins - genetics; Ions - chemistry; Molecular Dynamics Simulation; Mutation; Staphylococcus aureus - chemistry; Staphylococcus aureus - genetics
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/jp906790f

The α-hemolysin (αHL) 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 β-cyclodextrin (βCD) can insert into the αHL channel and significantly increase its anion selectivity. To understand how βCD can affect ion selectivity, molecular dynamics simulations and potential of mean force (PMF) calculations are carried out for different αHL channels with and without the βCD 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 βCD has no anion selectivity by itself but can increase the Cl− selectivity of the αHL channel when lodged into the pore lumen. Analysis shows that βCD 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.