To understand the mechanisms of Na(+)/Li(+) permeation at submicromolar Ca(2+) concentrations, Na(+)/Li(+) blocking at higher Ca(2+) concentrations (10(-6)-10(-4) M) and Ca(2+) permeation at millimolar Ca(2+) concentrations, we used our recently described L-type calcium channel model. For this purpose, we obtained potential of mean force (pmf) curves for the position change of one Na(+) and one Ca(2+) ion inside the channel and for the position change of a second Ca(2+) ion when the EEEE locus is coordinated to Ca(2+). The pmf curves suggest that (i) at submicromolar Ca(2+) concentrations, because of the low velocity of Ca(2+) entry in the channel, monovalent ion flux occurs; (ii) at Ca(2+) concentrations between 10(-6) and 10(-4) M, thermodynamic equilibrium between the channel and Ca(2+) is achieved; as the coordination of Ca(2+) with the locus is more favorable than the coordination of Na(+), the monovalent ion flux is blocked; and (iii) to put a second Ca(2+) ion inside the channel at an appropriate rate, the Ca(2+) concentration should reach millimolar levels. Nevertheless, the entry of a second Ca(2+) is thermodynamically unfavorable, indicating that the competition of two Ca(2+) ions for the locus leads to Ca(2+) permeation.