Is the G-Quadruplex an Effective Nanoconductor for Ions?

Abstract

We use a stepwise pulling protocol in molecular dynamics simulations to identify how a G-quadruplex selects and conducts Na(+), K(+), and NH4(+) ions. By estimating the minimum free-energy changes of the ions along the central channel via Jarzynski's equality, we find that the G-quadruplex selectively binds the ionic species in the following order: K(+) > Na(+) > NH4(+). This order implies that K(+) optimally fits the channel. However, the features of the free-energy profiles indicate that the channel conducts Na(+) best. These findings are in fair agreement with experiments on G-quadruplexes and reveal a profoundly different behavior from the prototype potassium-ion channel KcsA, which selects and conducts the same ionic species. We further show that the channel can also conduct a single file of water molecules and deform to leak water molecules. We propose a range for the conductance of the G-quadruplex.

K+ Block Is the Mechanism of Functional Asymmetry in Bacterial Nav Channels

“…After equilibration, step-wise pulling protocols [ 26 – 28 ] were used for non-equilibrium simulations of single-ion and three-ion configurations being pulled from the extracellular side of the membrane to the central cavity of the channel. The choice of the three-ion system was based on recent papers that investigated permeation mechanisms in depth.…”

“…Following each increment of λ i , a relaxation period was introduced in which the coordinates of the atoms of the system were unconstrained (see below). The soft harmonic pulling potential is useful to characterize the dynamically mutual responses between ions and the selectivity filter [ 26 , 28 ]. To remove any bad-energy contacts between the pulled ions and water molecules, energy minimization was run for 1000 steps at λ 0 = –20 Å, and NPT coupling was used for the rest of the simulations.…”

“…For a small system such as deca-alanine, a convergent free-energy change can be achieved with relaxation times as small as 0.4 ns [ 27 ]. For a system such as KcsA (PDB 1K4C) [ 26 ] and an 8-base nucleic acid G-quadruplex [ 28 ], relaxation times from 3 ns to 5 ns have been found to accurately distinguish the free-energy change of K + from that of Na + and to identify the differences in their selectivity mechanisms. The variance associated with the free-energy changes computed from this method can be estimated from [σ 2 W /Q+σ 4 W (k B T) -2 /2(Q-1)] 1/2 ≈ 1.0 kcal/mol, where σ W is a standard deviation of a work distribution function and Q is a number of data points in the work distribution.…”

Exploring ion induced folding of a single-stranded DNA oligomer from molecular simulation studies

“…Divalent ions are almost always required to stabilize the tertiary structures of nucleic acids. [15][16][17][18][19][20][21][22][23] However, limited attempts have been made to explore similar effects on ss-DNAs due to their conformational flexibility. 12,13 In other words, folded structures of DNA become stable in the presence of cations only.…”

Communication: Asymmetrical cation movements through G-quadruplex DNA

“…[17][18][19][20][21] Besides, both experimental methods and molecular dynamics (MD) simulations have proved that the cation-exchange between bulk solution and the cation coordination sites within a G-quadruplex is by passing along the axial channel of the quadruplex, rather than by moving through transient side openings in G-quartets. [22][23][24][25][26] It is also found from experiments that cation-exchange in G-quadruplex always shows an asymmetrical feature. For instance, NH + 4 ion exchange in the upper side of [d(G 3 T 4 G 4 )] 2 is 12 times faster than the lower side.…”