Simulation of water in a pore with charges: Application to a gating mechanism for ion channels

Abstract

The electric fields and potential in a pore filled with water are calculated, without using the Poisson-Boltzmann equation. No assumption of macroscopic dielectric behavior is made for the interior of the pore. The field and potential at any position in the pore are calculated for a charge in any other position in the pore, or the dielectric boundary of the pore. The water, represented by the polarizable PSPC model, is then placed in the pore, using a Monte Carlo simulation to obtain an equilibrium distribution. The water, charges, and dielectric boundary, together determine the field and potential distribution in the channel. The effect on an ion in the channel is then dependent on both the field, and the position and orientation of the water. The.channel can exist in two major configurations: open or closed, in which the open channel allows ions to pass. In addition, there may be intermediate states. The channel has a water filled pore, and a wall consisting of protein. The open or closed condition of the channel is determined without major conformational changes in the wall protein. Examples of the potential distribution in three dimensions, and the positions of the water molecules, are given for several charge configurations. It is suggested that the pK values of the amino acids in the protein are shifted by several units by the large potentials resulting from the charges which are present. The consequence is that many of the amino acids in the protein, on a particular segment (S4) of Na⁺ and K⁺ channels, which could bear a positive charge, are not charged. The protons may move from one amino acid to another by tunneling under the influence of the membrane potential, or upon depolarization of the membrane, which is the normal requirement for opening the channel.