Ion permeation through the alpha-hemolysin channel: theoretical studies based on Brownian dynamics and Poisson-Nernst-Plank electrodiffusion theory.

Identification of the molecular interaction governing ion conduction through biological pores is one of the most important goals of modern electrophysiology. Grand canonical Monte Carlo Brownian dynamics (GCMC/BD) and three-dimensional Poisson-Nernst-Plank (3d-PNP) electrodiffusion algorithms offer powerful and general approaches to study of ion permeation through wide molecular pores. A detailed analysis of ion flows through the staphylococcal alpha-hemolysin channel based on series of simulations at different concentrations and transmembrane potentials is presented. The position-dependent diffusion coefficient is approximated on the basis of a hydrodynamic model. The channel conductance calculated by GCMC/BD is approximately 10% higher than (electrophysiologically measured) experimental values, whereas results from 3d-PNP are always 30-50% larger. Both methods are able to capture all important electrostatic interactions in equilibrium conditions. The asymmetric conductance upon the polarity of the transmembrane potential observed experimentally is reproduced by GCMC/BD and 3d-PNP. The separation of geometrical and energetic influence of the channel on ion conduction reveals that such asymmetries arise from the permanent charge distribution inside the pore. The major determinant of the asymmetry is unbalanced charge in the triad of polar residues D127, D128, and K131. The GCMC/BD or 3d-PNP calculations reproduce also experimental reversal potentials and permeability rations in asymmetric ionic solutions. The weak anionic selectivity of the channel results from the presence of the salt bridge between E111 and K147 in the constriction zone. The calculations also reproduce the experimentally derived dependence of the reversible potential to the direction of the salt gradient. The origin of such effect arises from the asymmetrical distribution of energetic barriers along the channel axis, which modulates the preferential ion passage in different directions.