The role of electrostatics in ion premeation and selectivity of biological membrane channels

Electrostatics plays an important role in ion permeation and selectivity of biological membrane channels. Its rigorous treatment is of essence in computer simulations of such a complex macromolecular system in solution. Several novel approaches have been developed to handle long-range electrostatic interactions efficiently but yet accurately, based on an implicit solvent model, so-called the finite-difference Poisson-Boltzmann (PB) equation.;First, PB solvation forces are rigorously formulated and implemented to introduce the influence of an implicit solvent in molecular mechanics calculations of large biological systems. A series of numerical tests show that the calculated forces agree extremely well with finite-difference derivatives of the solvation free energy.;Second, the Generalized Solvent Boundary Potential (GSBP) approach is developed to allow accurate simulations of a small region of a large macromolecular system and incorporate the influence of the remaining distant atoms with an effective boundary potential. Based on a PB continuum model. GSBP includes the solvent-shielded static field from the distant atoms and the reaction field from the dielectric solvent. To gain a maximum efficiency, the reaction field is developed using a multipole basis-set expansion. Comparison with PB calculations shows that GSBP can accurately describe all electrostatic interactions and remain computationally inexpensive.;Third, a computational algorithm based on Grand Canonical Monte Carlo (GCMC) and Brownian Dynamics (BD) is developed to allow the simulation of ion channels with a realistic implementation of boundary conditions of concentration and transmembrane potential. Similar to GSBP, a PB continuum model and a basis-set expansion are used to calculate the multi-ion potential of mean force. Calculated channel conductance and selectivity of E. coli OmpF porin show remarkable agreements with the experimental data.;A 5 nanosecond all-atom molecular dynamics trajectory of OmpF porin embedded in an explicit-dimyristoyl-phosphatidylcholine (DMPC) bilayer bathed by a 1M [KCl] aqueous salt solution is generated to explore the microscopic details of the mechanism of ion permeation. It is observed that instantaneous displacements of K+ and Cl- ions inside the OmpF pore appear to be random and slowed relative to those in the bulk, but the ions follow well-separated specific pathways guided by the electrostatic potential arising from the protein charges. In particular, the presence of K + ions in the pore appears to be necessary to help the translocation of Cl- ions by formation of ion pairs.