^{1}, Niall J. English

^{1,a)}and J. M. D. MacElroy

^{1}

### Abstract

Water self-diffusion within human aquaporin 4 has been studied using molecular dynamics (MD) simulations in the absence and presence of external ac and dc electric fields. The computed diffusive (*p* _{ d }) and osmotic (*p* _{ f }) permeabilities under zero-field conditions are (0.718 ± 0.24) × 10^{−14} cm^{3} s^{−1} and (2.94 ± 0.47) × 10^{−14} cm^{3} s^{−1}, respectively; our *p* _{ f } agrees with the experimental value of (1.50 ± 0.6) × 10^{−14} cm^{3} s^{−1}. A gating mechanism has been proposed in which side-chain dynamics of residue H201, located in the selectivity filter, play an essential role. In addition, for nonequilibrium MD in external fields, it was found that water dipole orientation within the constriction region of the channel is affected by electric fields (e-fields) and that this governs the permeability. It was also found that the rate of side-chain flipping motion of residue H201 is increased in the presence of e-fields, which influences water conductivity further.

We thank Raúl Araya Sechi for all of his help and useful discussions, and Science Foundation Ireland and the Irish Centre for High-End Computing for the provision of computational resources.

I. INTRODUCTION

II. METHODOLOGY

A. Modeling

B. Diffusive and osmotic water permeabilities

C. Water orientation

D. Selectivity filter dynamics

III. RESULTS

A. h-AQP4 equilibrium MD

B. h-AQP4 water dynamics under electric field conditions

C. Gating dynamics and electric fields

D. Water dipole orientation disruption

IV. CONCLUSIONS

### Key Topics

- Polymers
- 21.0
- Molecular dynamics
- 11.0
- Static electric fields
- 11.0
- Electric fields
- 9.0
- Lipids
- 7.0

## Figures

(a) Cartoon representation of h-AQP4 loaded with water (in its dipolar orientation) and the direction of the electric fields. Residues H201, R216, G93, and I193 are represented in blue licorice form, and show the upper and lower limits of the channel constriction region. N213 and N97 from the conserved NPA region are depicted in cyan licorice representation. (b) Cross section of the periodic cell simulated. (c) Top view of the simulated system.

(a) Cartoon representation of h-AQP4 loaded with water (in its dipolar orientation) and the direction of the electric fields. Residues H201, R216, G93, and I193 are represented in blue licorice form, and show the upper and lower limits of the channel constriction region. N213 and N97 from the conserved NPA region are depicted in cyan licorice representation. (b) Cross section of the periodic cell simulated. (c) Top view of the simulated system.

(left) Average pore radius profile along the axis for the four pores calculated with the program HOLE (Ref. 56) for zero-field simulation. (right) MD snapshot matching the pore radius profile.

(left) Average pore radius profile along the axis for the four pores calculated with the program HOLE (Ref. 56) for zero-field simulation. (right) MD snapshot matching the pore radius profile.

(a) Cumulative complete permeation events for the whole tetramer, along *z* + (*N* +), *z* − (*N* −) and their sum (*Nt*) for zero-field MD. (b) Averaged water molecule orientation inside the channel C.R. for zero-field MD. The error bars are obtained from the variance among the four monomers. (c) and (d) Trajectories of the collective coordinate *n*(*t*), Eqs. (6)–(8), and the MSDs of *n*(*t*), Eq. (9), respectively. The black monomer represents A, the red monomer B, the green monomer C, and the blue monomer D, while lines in (d) are linear regression lines superimposed on each MSD curve.

(a) Cumulative complete permeation events for the whole tetramer, along *z* + (*N* +), *z* − (*N* −) and their sum (*Nt*) for zero-field MD. (b) Averaged water molecule orientation inside the channel C.R. for zero-field MD. The error bars are obtained from the variance among the four monomers. (c) and (d) Trajectories of the collective coordinate *n*(*t*), Eqs. (6)–(8), and the MSDs of *n*(*t*), Eq. (9), respectively. The black monomer represents A, the red monomer B, the green monomer C, and the blue monomer D, while lines in (d) are linear regression lines superimposed on each MSD curve.

Time evolution of the dihedral angle ∠*C* − *C* _{α} − *C* _{β} − *C* _{γ} of H201 for each monomer, for all simulations. Zero denotes equilibrium (zero-field) MD. EFZ are all simulations applied in the *z*-direction, i.e., along the pore axis, while EFY are all simulations applied in the *y*-direction, i.e., perpendicular to the pore axis. The left-column numbers are all the ac fields’ frequencies studied (in GHz). The letters denote the correspondingly labeled monomers.

Time evolution of the dihedral angle ∠*C* − *C* _{α} − *C* _{β} − *C* _{γ} of H201 for each monomer, for all simulations. Zero denotes equilibrium (zero-field) MD. EFZ are all simulations applied in the *z*-direction, i.e., along the pore axis, while EFY are all simulations applied in the *y*-direction, i.e., perpendicular to the pore axis. The left-column numbers are all the ac fields’ frequencies studied (in GHz). The letters denote the correspondingly labeled monomers.

Single-channel cumulative complete permeation events for all simulations, along *z* + (*N* + ), *z* − (*N* − ), and their sum (*Nt*). Zero denotes equilibrium (zero-field) MD. EFZ are all simulations applied in the *z*-direction, i.e., along the pore axis, while EFY are all simulations applied in the *y*-direction, i.e., perpendicular to the pore axis. The left-column numbers are all the ac fields’ frequencies studied (in GHz). The letters denote the correspondingly labeled monomer.

Single-channel cumulative complete permeation events for all simulations, along *z* + (*N* + ), *z* − (*N* − ), and their sum (*Nt*). Zero denotes equilibrium (zero-field) MD. EFZ are all simulations applied in the *z*-direction, i.e., along the pore axis, while EFY are all simulations applied in the *y*-direction, i.e., perpendicular to the pore axis. The left-column numbers are all the ac fields’ frequencies studied (in GHz). The letters denote the correspondingly labeled monomer.

Single channel averaged water molecule orientation inside the channel C.R. Zero denotes equilibrium (zero-field) MD. EFZ are all simulations applied in the *z*-direction, i.e., along the pore axis, while EFY are all simulations applied in the *y*-direction, i.e., perpendicular to the pore axis. The left-column numbers are all the *e*/*m* fields’ frequencies studied (in GHz). The letters denote the correspondingly labeled monomers.

Single channel averaged water molecule orientation inside the channel C.R. Zero denotes equilibrium (zero-field) MD. EFZ are all simulations applied in the *z*-direction, i.e., along the pore axis, while EFY are all simulations applied in the *y*-direction, i.e., perpendicular to the pore axis. The left-column numbers are all the *e*/*m* fields’ frequencies studied (in GHz). The letters denote the correspondingly labeled monomers.

## Tables

Single channel osmotic and diffusive permeabilities (*p* _{ f }, *p* _{ d } in 10^{−14} cm^{3} s^{−1}) for zero-field MD and in dc and ac electric fields applied along the *z*-direction, i.e., along the pore axis.

Single channel osmotic and diffusive permeabilities (*p* _{ f }, *p* _{ d } in 10^{−14} cm^{3} s^{−1}) for zero-field MD and in dc and ac electric fields applied along the *z*-direction, i.e., along the pore axis.

Single channel osmotic and diffusive permeabilities (*p* _{ f }, *p* _{ d } in 10^{−14} cm^{3} s^{−1}) for zero-field MD and in dc and ac electric fields applied along the *y*-direction, i.e., perpendicular to the pore axis.

Single channel osmotic and diffusive permeabilities (*p* _{ f }, *p* _{ d } in 10^{−14} cm^{3} s^{−1}) for zero-field MD and in dc and ac electric fields applied along the *y*-direction, i.e., perpendicular to the pore axis.

Article metrics loading...

Full text loading...

Commenting has been disabled for this content