The effect of protein dielectric coefficient on the ionic selectivity of a calcium channel

Abstract

Calcium-selective ion channels are known to have carboxylate-rich selectivity filters, a common motif that is primarily responsible for their high Ca(2+) affinity. Different Ca(2+) affinities ranging from micromolar (the L-type Ca channel) to millimolar (the ryanodine receptor channel) are closely related to the different physiological functions of these channels. To understand the physical mechanism for this range of affinities given similar amino acids in their selectivity filters, we use grand canonical Monte Carlo simulations to assess the binding of monovalent and divalent ions in the selectivity filter of a model Ca channel. We use a reduced model where the electolyte is modeled by hard-sphere ions embedded in a continuum dielectric solvent, while the interior of protein surrounding the channel is allowed to have a dielectric coefficient different from that of the electrolyte. The induced charges that appear on the protein/lumen interface are calculated by the induced charge computation method [Boda et al., Phys. Rev. E 69, 046702 (2004)]. It is shown that decreasing the dielectric coefficient of the protein attracts more cations into the pore because the protein's carboxyl groups induce negative charges on the dielectric boundary. As the density of the hard-sphere ions increases in the filter, Ca(2+) is absorbed into the filter with higher probability than Na(+) because Ca(2+) provides twice the charge to neutralize the negative charge of the pore (both structural carboxylate oxygens and induced charges) than Na(+) while occupying about the same space (the charge/space competition mechanism). As a result, Ca(2+) affinity is improved an order of magnitude by decreasing the protein dielectric coefficient from 80 to 5. Our results indicate that adjusting the dielectric properties of the protein surrounding the permeation pathway is a possible way for evolution to regulate the Ca(2+) affinity of the common four-carboxylate motif.

Molecular dynamics simulations of potassium channels

“…Besides molecular dynamics simulations, described before, stochastic dynamics [79][80][81] and continuum theories [82][83][84][85][86] have been widely used. The reader is referred to this review for further details.…”

A method for treating the passage of a charged hard sphere ion as it passes through a sharp dielectric boundary

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] The dielectric boundaries usually were hard impenetrable walls or ions were excluded from their vicinity by other walls or some repulsion potential. Even when the possibility of ions crossing dielectric boundaries is otherwise a physical reality, authors decided to avoid such events in their simulations in one way or other.…”

“…In our ion channel simulations, 11,12,14,17 we used a dielectric coefficient inside the channel that was equal to that of the bath. A similar approach was followed by Coalson and co-workers.…”

“…Various boundary element methods (BEM) in apparent surface charge (ASC) calculations were widely used to compute induced charges. 32,33 A variational formalism has been proposed by Allen et al 34 Inspired by this paper, a method called the induced charge computation (ICC) method was proposed by us 8,11 and used to study DLs 9 and ion channels 11,12,14,17 with Monte Carlo (MC) simulations. In all these studies, the ions stayed in their native dielectric; they did not cross dielectric boundaries.…”

Response to “Comment on ‘The nonmonotonic concentration dependence of the mean activity coefficient of electrolytes is a result of a balance between solvation and ion–ion correlations’” [J. Chem. Phys. 134, 157101 (2011)]

“…Actually, that is what we do in our ion channel studies, for example. 7 There are parameters, however, whose values are well-defined so they should not be adjusted. Even if we adjust a parameter, the resulting value should have a sensible physical meaning.…”