The role of several fragments of the potassium channel KcsA has been examined by the Poisson−Nernst−Planck (PNP) theory. The efficiency of the computational method allowed comparing a large number of channel models, with different intracellular gate openings, partial atomic charges, and amino acid sequences. Perhaps counter-intuitively, the calculated ion current decreases when the mean radius of the entrance cavity increases. Widening of the vestibule, in fact, increases the volume accessible to water, which is the volume with a high dielectric constant. In turn, water screens the attractive charges of the P-loop backbone. The backbone charges of the M2 helixes instead oppose the entrance of potassium ions through a complicated mechanism that can be separated in the activity of two interfering dipoles. The conductance of the KcsA models increased when two neutral residues in M2 were mutated to glutamic acid, in agreement with experimental results (Brelidze, T. I.; Niu, X.; Magleby, K. L. PNAS2003, 100, 9017−9022). As a general conclusion, a relation between channel conductance and potassium concentration in the intracellular cavity emerged. Although the ion transport is the result of the fine balance of a number of different effects, the experimental results can be reproduced quantitatively only on the basis of electrostatic forces, which are the only driving forces modeled by the PNP theory. [ABSTRACT FROM AUTHOR]