Monocation-driven proton transfer relays within G protein-coupled receptors of the rhodopsin class and the GTP synthase mechanism

Proton relay mechanisms involving acidic residues sited 10–12 A apart within a general hydrophobic environment of a G protein ternary complex are examined for potential ligand-activated proton transport. Extended basis set calculations on Arg-Asp, Lys-Asp, Arg-Cys, Lys-Cys and potential His-Asp interactions are intrinsically dominated by preferred neutral hydrogen bonded complexes over their ion pair form. The early concept of ‘membrane-delimited monocation transfer’ associated with the stimulant action of ligands is identified with a potential monocation channel operating through the ternary complex where the monocation provides the driving force for the set of relays, each relay producing simple Na+ or K+/H+ exchange. Under the influence of the cation the ligand, nor-adrenaline, in the β1-adrenergic receptor is then seen to act as a shuttle between two relays involving aspartate residues on the receptor’s α-helices III and II and delivers two protons through two relays returning towards the periplasm as a catechol anion. A set of proton transfer relays are identified within the G protein-coupled receptor complex which will convey a proton some 56 A from an aspartate residue on α-helix III to a glutamate residue at the G protein cytoplasmic interface. This residue at the base of the Gα α2-helix is identified as the candidate residue for phosphorylation by many regulatory G protein signalling [RGS] proteins and defines the phosphorylated residue which, on proton activation, can transfer its metaphosphate group to the GTP held within the Gα protein supporting a GTP synthase mechanism. The attachment of the Gαβγ heterotrimer to the β1-adrenergic receptor based on the positioning of extended receptor α-helices V, VI and the N-terminal α-helix of the Gsα-adapted protein within opposing clefts of the Gαβγ heterotrimer was found accurate for development of the relay mechanisms for mammalian receptors. The proposed monocation channel pathway is X-ray based but the completion of the proton transfer relay at the G protein–receptor interface utilised the Gsα C-terminal acid group necessitating movement of four C-terminal residues from the Gα.GTPγS X-ray structure. The model may be applied to both mammalian- and bacteriorhodopsin provided that the initial large dipole theoretically developed within the rhodopsin on absorption allows ligand movement to align itself with the potential gradient across the membrane. The delivery of two protons in the case of bovine rhodopsin towards the cytoplasm and in bacteriorhodopsin towards the periplasm with the respective monocation-assisted movement as carbanions can be supported by the expected isomers formed by electron deficient (trans) or electron rich (cis) backbones of the highly polarizable rhodopsin due to σ bond hyperconjugation. Proton relay mechanisms involving acidic residues sited 10–12 A apart within a general hydrophobic environment of a G protein ternary complex are examined for potential ligand-activated proton transport. Extended basis set calculations on Arg-Asp, Lys-Asp, Arg-Cys, Lys-Cys and potential His-Asp interactions are intrinsically dominated by preferred neutral hydrogen bonded complexes over their ion pair form. The early concept of ‘membrane-delimited monocation transfer’ associated with the stimulant action of ligands is identified with a potential monocation channel operating through the ternary complex where the monocation provides the driving force for the set of relays, each relay producing simple Na+ or K+/H+ exchange. Under the influence of the cation the ligand, nor-adrenaline, in the β1-adrenergic receptor is then seen to act as a shuttle between two relays involving aspartate residues on the receptor’s α-helices III and II and delivers two protons through two relays returning towards the periplasm as a catechol anion. A set of proton transfer relays are identified within the G protein-coupled receptor complex which will convey a proton some 56 A from an aspartate residue on α-helix III to a glutamate residue at the G protein cytoplasmic interface. This residue at the base of the Gα α2-helix is identified as the candidate residue for phosphorylation by many regulatory G protein signalling [RGS] proteins and defines the phosphorylated residue which, on proton activation, can transfer its metaphosphate group to the GTP held within the Gα protein supporting a GTP synthase mechanism. The attachment of the Gαβγ heterotrimer to the β1-adrenergic receptor based on the positioning of extended receptor α-helices V, VI and the N-terminal α-helix of the Gsα-adapted protein within opposing clefts of the Gαβγ heterotrimer was found accurate for development of the relay mechanisms for mammalian receptors. The proposed monocation channel pathway is X-ray based but the completion of the proton transfer relay at the G protein–receptor interface utilised the Gsα C-terminal acid group necessitating movement of four C-terminal residues from the Gα.GTPγS X-ray structure. The model may be applied to both mammalian- and bacteriorhodopsin provided that the initial large dipole theoretically developed within the rhodopsin on absorption allows ligand movement to align itself with the potential gradient across the membrane. The delivery of two protons in the case of bovine rhodopsin towards the cytoplasm and in bacteriorhodopsin towards the periplasm with the respective monocation-assisted movement as carbanions can be supported by the expected isomers formed by electron deficient (trans) or electron rich (cis) backbones of the highly polarizable rhodopsin due to σ bond hyperconjugation.