Protein Engineering, Vol. 16, No. 3, 209-215,
March 2003
© 2003 Oxford University Press
Potential of mean force calculations on an L-type calcium channel model
Physical Organic Chemistry Group, Departamento de Química Orgânica, Instituto de Química, UFRJ, Bloco A, Sala 609, Cidade Universitária, Ilha do Fundão, CT, RJ 21949-900, Rio de Janeiro, Brazil
1 To whom correspondence should be addressed. Present address: Department of Chemistry, Wesleyan University, Middletown,CT 06459, USA. E-mail: gbarreiro{at}wesleyan.edu
To understand the mechanisms of Na+/Li+ permeation at submicromolar Ca2+ concentrations, Na+/Li+ blocking at higher Ca2+ concentrations (10-6–10-4 M) and Ca2+ permeation at millimolar Ca2+ 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 Ca2+ ion inside the channel and for the position change of a second Ca2+ ion when the EEEE locus is coordinated to Ca2+. The pmf curves suggest that (i) at submicromolar Ca2+ concentrations, because of the low velocity of Ca2+ entry in the channel, monovalent ion flux occurs; (ii) at Ca2+ concentrations between 10-6 and 10-4 M, thermodynamic equilibrium between the channel and Ca2+ is achieved; as the coordination of Ca2+ with the locus is more favorable than the coordination of Na+, the monovalent ion flux is blocked; and (iii) to put a second Ca2+ ion inside the channel at an appropriate rate, the Ca2+ concentration should reach millimolar levels. Nevertheless, the entry of a second Ca2+ is thermodynamically unfavorable, indicating that the competition of two Ca2+ ions for the locus leads to Ca2+ permeation.