title: The inhibition of glycerol permeation through aquaglyceroporin-3 induced by mercury(II): A molecular dynamics study.
abstract: Mercurial compounds are known to inhibit water permeation through aquaporins (AQPs). Although in the last years some hypotheses were proposed, the exact mechanism of inhibition is still an open question and even less is known about the inhibition of the glycerol permeation through aquaglyceroporins. Molecular dynamics (MD) simulations of human aquaporin-3 (AQP3) have been performed up to 200ns in the presence of Hg(2+) ions. For the first time, we have observed the unbiased passage of a glycerol molecule from the extracellular to cytosolic side. Moreover, the presence of Hg(2+) ions covalently bound to Cys40 leads to a collapse of the aromatic/arginine selectivity filter (ar/R SF), blocking the passage of both glycerol and water. Interestingly, the local conformational changes of the protein follow mercury coordination by water and by aminoacidic donor atoms. Overall, the obtained results are important to improve the design of selective AQP inhibitors for future therapeutic and imaging applications.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16, 90128, Palermo, Italy; Istituto EuroMediterraneo di Scienza e Tecnologia (IEMEST), Via Emerico Amari 123, 90139, Palermo, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Spinello
authors.affiliation: Dept. Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, A. Deusinglaan 1, 9731AV Groningen, The Netherlands.
authors.forename: Andreia
authors.initials: A
authors.lastname: de Almeida
authors.affiliation: Dept. Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, A. Deusinglaan 1, 9731AV Groningen, The Netherlands; School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom. Electronic address: CasiniA@cardiff.ac.uk.
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16, 90128, Palermo, Italy; Istituto EuroMediterraneo di Scienza e Tecnologia (IEMEST), Via Emerico Amari 123, 90139, Palermo, Italy. Electronic address: giampaolo.barone@unipa.it.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Barone
mesh_terms: D051400:Aquaporin 3 / Q000737:chemistry* / Q000378:metabolism; D020346:Aquaporins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport; D002413:Cations, Divalent; D002463:Cell Membrane Permeability; D004926:Escherichia coli / Q000737:chemistry; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism; D005990:Glycerol / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008567:Membranes, Artificial; D008628:Mercury / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000737:chemistry; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein; D014867:Water / Q000737:chemistry* / Q000378:metabolism
chemical_list: C496027:AQP3 protein, human; D020346:Aquaporins; D002413:Cations, Divalent; D029968:Escherichia coli Proteins; D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D014867:Water; C078043:GlpF protein, E coli; D051400:Aquaporin 3; D008628:Mercury; D005990:Glycerol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: Aquaglyceroporin; Glycerol permeation; Mercury; Molecular dynamics; Water permeation