Dynamics and energetics of solute permeation through the Plasmodium falciparum aquaglyceroporin

Abstract

The aquaglyceroporin from Plasmodium falciparum (PfAQP) is a potential drug target for the treatment of malaria. It efficiently conducts water and other small solutes, and is proposed to intervene in several crucial physiological processes during the parasitic life cycle. Despite the wealth of experimental data available, a dynamical and energetic description at the single-molecule level of the solute permeation through PfAQP has been lacking so far. Here we address this question by using equilibrium and umbrella sampling molecular dynamics simulations. We computed the water osmotic permeability coefficient, the pore geometry and the potential of mean force for the permeation of water, glycerol and urea. Our simulations show that the PfAQP, the human aquaporin 1 (hAQP1) and the Escherichia coli glycerol facilitator (GlpF) have nearly identical water permeabilities. The Arg196 residue at the ar/R region was found to play a crucial role regulating the permeation of water, glycerol and urea. The computed free energy barriers at the ar/R selectivity filter corroborate that PfAQP conducts glycerol at higher rates than urea, and suggest that PfAQP is a more efficient glycerol and urea channel than GlpF. Our results are consistent with a solute permeation mechanism for PfAQP which is similar to the one established for other members of the aquaglyceroporin family. In this mechanism, hydrophobic regions near the NPA motifs are the main water rate limiting barriers, and the replacement of water-arg196 interactions and solute-matching in the hydrophobic pocket at the ar/R region are the main determinants underlying selectivity for the permeation of solutes like glycerol and urea.

Glycerol modulates water permeation through Escherichia coli aquaglyceroporin GlpF

“…At 0 μM glycerol concentration, GlpF's conducting pore will be glycerol-free. The PMF of water permeation was determined to be flat throughout the open channel, having a low Arrhenius barrier, $E_a^0<4\text{kcal}/\text{mol}$ [20,27,31], similar to that of AQPZ [14]. …”

“…In vitro experiments demonstrated that the water permeation rate in the range of glycerol concentration up to 100 mM was much lower than the water-specific aquaporins (including AQPZ) [13,14,30], but theoretical studies showed that the rate of water permeation through GlpF in absence of glycerols is similar to or greater than through AQPZ [23,31]. This puzzling point actually serves to validate our theory: Water permeation through glycerol-bound GlpF is much slower than through apo GlpF because a glycerol bound inside GlpF's conducting channel occludes waters and the dissociation of this bound glycerol is a much slower process than that of a water traversing the glycerol-free channel of GlpF.…”

“…And, related to this question, there are some unsolved issues about water permeation through this protein's conducting pore: The in vitro data indicate that GlpF is much less permeable to water than E. coli aquaporin Z (AQPZ) and other water-selective aquaporins are [13,14,30], but theoretical studies predict that GlpF is more permeable than AQPZ etc. [23,31]; The in vitro experiments show that water permeation has an Arrhenius activation barrier that is about 7 kcal/mol [13], but the theoretical studies all give a rather flat free-energy profile throughout the permeation channel of GlpF [20,27]. While the in vitro experiments indicate that the presence of up to 100 mM glycerol does not affect the kinetics of water transport [13], all in silico studies are limited to 0 M glycerol concentration.…”

MIPModDB: a central resource for the superfamily of major intrinsic proteins

“…These residues are contributed by second and fifth TM segments and loop E. This aromatic/arginine (ar/R) selectivity filter has been implicated in obstructing the proton conduction (62) and efficient solute transport (37,63,64). The four ar/R selectivity filter residues, represented by their one letter codes, are given for each MIP.…”

Erythritol predicted to inhibit permeation of water and solutes through the conducting pore of P. falciparum aquaporin

“…1) and the Escherichia coli aquaglyceroporin GlpF[10, 16-19]. In absence of glycerol, in vitro experiments showed that water easily traverses the conducting pore of PfAQP[8] and in silico studies corroborated it with a flat landscape of its free energy[17, 20, 21]. In presence of glycerol, in vitro data showed reduced water permeability of PfAQP.…”