title: Mechanism of NH4(+) Recruitment and NH3 Transport in Rh Proteins.
abstract: In human cells, membrane proteins of the rhesus (Rh) family excrete ammonium and play a role in pH regulation. Based on high-resolution structures, Rh proteins are generally understood to act as NH3 channels. Given that cell membranes are permeable to gases like NH3, the role of such proteins remains a paradox. Using molecular and quantum mechanical calculations, we show that a crystallographically identified site in the RhCG pore actually recruits NH4(+), which is found in higher concentration and binds with higher affinity than NH3, increasing the efficiency of the transport mechanism. A proton is transferred from NH4(+) to a signature histidine (the only moiety thermodynamically likely to accept a proton) followed by the diffusion of NH3 down the pore. The excess proton is circulated back to the extracellular vestibule through a hydrogen bond network, which involves a highly conserved and functionally important aspartic acid, resulting in the net transport of NH3.
authors.affiliation: SIB Swiss Institute of Bioinformatics, Klingelbergstrasse 50/70, 4056 Basel, Switzerland; Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Sefer
authors.initials: S
authors.lastname: Baday
authors.affiliation: Department of Chemistry and Biochemistry, Centre for Research in Molecular Modeling (CERMM), Concordia University, 7141 Sherbrooke Street West, Montréal, QC H4B 1R6, Canada.
authors.forename: Esam A
authors.initials: EA
authors.lastname: Orabi
authors.affiliation: Department of Chemistry and Biochemistry, Centre for Research in Molecular Modeling (CERMM), Concordia University, 7141 Sherbrooke Street West, Montréal, QC H4B 1R6, Canada.
authors.forename: Shihao
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, Centre for Research in Molecular Modeling (CERMM), Concordia University, 7141 Sherbrooke Street West, Montréal, QC H4B 1R6, Canada. Electronic address: guillaume.lamoureux@concordia.ca.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lamoureux
authors.affiliation: SIB Swiss Institute of Bioinformatics, Klingelbergstrasse 50/70, 4056 Basel, Switzerland; Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland. Electronic address: simon.berneche@isb-sib.ch.
authors.forename: Simon
authors.initials: S
authors.lastname: Bernèche
mesh_terms: D000641:Ammonia / Q000737:chemistry* / Q000378:metabolism; D001224:Aspartic Acid / Q000737:chemistry* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D006639:Histidine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D055503:Protein Multimerization; D011522:Protons; D011789:Quantum Theory; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D027682:Cation Transport Proteins; D008562:Membrane Glycoproteins; D011522:Protons; C413213:RHCG protein, human; D001224:Aspartic Acid; D006639:Histidine; D000641:Ammonia; D004134:Dimyristoylphosphatidylcholine