Mechanisms of Permeation and Selectivity in Calcium Channels

Abstract

The mechanisms underlying ion transport and selectivity in calcium channels are examined using electrostatic calculations and Brownian dynamics simulations. We model the channel as a rigid structure with fixed charges in the walls, representing glutamate residues thought to be responsible for ion selectivity. Potential energy profiles obtained from multi-ion electrostatic calculations provide insights into ion permeation and many other observed features of L-type calcium channels. These qualitative explanations are confirmed by the results of Brownian dynamics simulations, which closely reproduce several experimental observations. These include the current-voltage curves, current-concentration relationship, block of monovalent currents by divalent ions, the anomalous mole fraction effect between sodium and calcium ions, attenuation of calcium current by external sodium ions, and the effects of mutating glutamate residues in the amino acid sequence.

Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel

“…During the entire conduction process, the largest free energy barrier encountered is ∼1.2 kcal/mol during the transition from C 3 to F (perhaps slightly elevated due to the closed gate), allowing for rapid conduction. This three-ion mechanism is supported by previous studies of simplified Glu-lined pores (13), and by recent simulations (23), but not in other studies that focused on a twoion process (21,22).…”

“…This Na + selectivity emerging from a Glu-lined pore leads us to question the mechanism by which these channels optimally conduct Na + ions. Simple physical models have proposed a charge/space competition theory to explain the variable Na + /Ca 2+ selectivity of Glu-lined SFs, where the volume and electrostatic environment both play a role in the number of ions that the channels can bind and efficiently conduct (10,12,13). Selectivity between the monovalent cations Na + and K + may be interpreted in terms of ligand field strength (14), where amide carbonyls provide weaker fields that favor larger ions, like K + , whereas carboxylates create a high field strength site (S HFS ) (6) favorable to Na + .…”

Differences in Apparent Pore Sizes of Low and High Voltage-activated Ca2+ Channels

“…It is notable that this holds for T-type channels as well as L-type channels (35,36,50) because T-type Ca 2ϩ channels, like HVA channels, are highly selective for their ion of choice under physiological conditions. Taken together, these findings are relevant to current efforts at approaching Ca 2ϩ channel permeation with experiments (55,61,62) and theoretical calculations (63)(64)(65)(66)(67).…”

Diffusion constant of K+ inside Gramicidin A: A comparative study of four computational methods

“…(9) associated with the GLE-HO method, the normalized VACF C(t) can be found by inverse Laplace transformation of a function that contains the Laplace transform of the memory function, namely: (14) We calculated C(t) using the above equation with the analytic form of M̂ (s) described above. Alternatively, C(t) was calculated directly from MD simulations of K + restrained with the same harmonic force constant as used to calculate C(t) analytically (i.e., Eq.…”

“…With the availability of detailed atomistic structures of several ion channels (Gramicidin A (GA) [1], KcsA potassium channel [2], α-hemolysin [3], ClC chloride channel [4]) it has become feasible to do accurate theoretical modeling of ion currents in order to understand the mechanisms of ion transport through biological channels. At present, the most popular methods of ion current modeling are PoissonNernst-Planck (PNP) [5][6][7][8][9][10], Brownian Dynamics (BD) [11][12][13][14][15][16] and Non-equilibrium Molecular dynamics (NEMD) [17][18][19]. Of these methods PNP is the most primitive but fastest method.…”