title: Erythritol predicted to inhibit permeation of water and solutes through the conducting pore of P. falciparum aquaporin.
abstract: Plasmodium falciparum aquaporin (PfAQP) is a multifunctional channel protein in the plasma membrane of the malarial parasite that causes the most severe form of malaria infecting more than a million people a year. This channel protein facilitates transport of water and several solutes across the cell membrane. In order to better elucidate the fundamental interactions between PfAQP and its permeants and among the permeants, I conducted over three microseconds in silico experiments of atomistic models of the PfAQP-membrane system to obtain the free-energy profiles of five permeants (erythritol, water, glycerol, urea, and ammonia) throughout the amphipathic conducting pore of PfAQP. The profiles are analyzed in light of and shown to be consistent with the existent in vitro data. The binding affinities are computed using the free-energy profiles and the permeant fluctuations inside the channel. On this basis, it is predicted that erythritol, a permeant of PfAQP itself having a deep ditch in its permeation passageway, inhibits PfAQP's functions of transporting water and other solutes with an IC50 in the range of high nanomolars. This leads to the possibility that erythritol, a sweetener generally considered safe, may inhibit or kill the malarial parasite in vivo without causing undesired side effects. Experimental studies are hereby called for to directly test this theoretical prediction of erythritol strongly inhibiting PfAQP in vitro and possibly inhibiting P. falciparum in vivo.
authors: Department of Physics, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA. Electronic address: Liao.Chen@utsa.edu.
authors: Liao Y
authors: LY
authors: Chen
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000378:metabolism*; D004896:Erythritol / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D010539:Permeability; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D014867:Water / Q000378:metabolism*
chemical_list: D020346:Aquaporins; D014867:Water; D004896:Erythritol
keywords: Aqua(glycero)porin; Channel-transport regulation; Free energy; Malarial parasite; Polyol–protein interaction
references: J Comput Chem. 2010 Mar;31(4):671-90
references: 19575467
references: Nat Struct Mol Biol. 2008 Jun;15(6):619-25
references: 18500352
references: Phys Chem Chem Phys. 2011 Apr 7;13(13):6176-83
references: 21359274
references: Biochem Biophys Res Commun. 2011 Sep 9;412(4):654-9
references: 21856282
references: Biochim Biophys Acta. 2012 May;1818(5):1218-24
references: 22326891
references: Mol Aspects Med. 2012 Oct-Dec;33(5-6):514-7
references: 22542572
references: J Struct Biol. 2013 Jan;181(1):71-6
references: 23108237
references: Biochim Biophys Acta. 2013 Aug;1828(8):1786-93
references: 23506682
references: Biochim Biophys Acta. 2014 May;1840(5):1566-73
references: 24140393
references: Nat Rev Drug Discov. 2014 Apr;13(4):259-77
references: 24625825
references: Biochim Biophys Acta. 2014 Dec;1838(12):3052-60
references: 25150048
references: Science. 2000 Oct 20;290(5491):481-6
references: 11039922
references: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2888-93
references: 11226336
references: J Mol Graph Model. 2001;19(1):13-25
references: 11381523
references: Science. 2001 Dec 14;294(5550):2353-7
references: 11743202
references: Biopolymers. 2000-2001;56(4):257-65
references: 11754339
references: J Biol Chem. 2002 Feb 15;277(7):4874-82
references: 11729204
references: Int Rev Cytol. 2002;215:75-104
references: 11952238
references: Science. 2002 Apr 19;296(5567):525-30
references: 11964478
references: J Synchrotron Radiat. 2004 Jan 1;11(Pt 1):86-8
references: 14646142
references: Biophys J. 2004 Jan;86(1 Pt 1):50-7
references: 14695248
references: Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1153-8
references: 14734807
references: PLoS Biol. 2003 Dec;1(3):E72
references: 14691544
references: Biophys J. 1997 Mar;72(3):1047-69
references: 9138555
references: J Biol Chem. 1998 Jun 12;273(24):14659-62
references: 9614059
references: Biophys J. 1999 Jul;77(1):139-53
references: 10388746
references: Pflugers Arch. 2005 Sep;450(6):415-28
references: 15988592
references: J Comput Chem. 2005 Dec;26(16):1781-802
references: 16222654
references: J Chem Phys. 2004 Apr 1;120(13):5946-61
references: 15267476
references: Biochemistry. 1992 Aug 25;31(33):7436-40
references: 1510932
references: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references: 8744570
references: Mol Microbiol. 2006 Sep;61(6):1598-608
references: 16889642
references: Biochim Biophys Acta. 2006 Aug;1758(8):1012-7
references: 16427024
references: Biophys Chem. 2006 Dec 1;124(3):251-67
references: 16781050
references: Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1198-203
references: 18202181
references: J Chem Phys. 2008 Oct 14;129(14):144113
references: 19045140
references: Handb Exp Pharmacol. 2009;(190):3-28
references: 19096770
references: J Comput Chem. 2009 Jul 30;30(10):1545-614
references: 19444816
references: Protein Expr Purif. 2008 May;59(1):69-78
references: 18295508
references: Phys Chem Chem Phys. 2010 Sep 21;12(35):10246-54
references: 20607193