title: Enthalpic signature of methonium desolvation revealed in a synthetic host-guest system based on cucurbit[7]uril.
abstract: Methonium (N(+)Me3) is an organic cation widely distributed in biological systems. As an organic cation, the binding of methonium to protein receptors requires the removal of a positive charge from water. The appearance of methonium in biological transmitters and receptors seems at odds with the large unfavorable desolvation free energy reported for tetramethylammonium (TMA(+)), a frequently utilized surrogate of methonium. Here, we report an experimental system that facilitates incremental internalization of methonium within the molecular cavity of cucurbit[7]uril (CB[7]). Using a combination of experimental and computational studies, we show that the transfer of methonium from bulk water (partially solvated methonium state) to the CB[7] cavity (mostly desolvated methonium state) is accompanied by a remarkably small desolvation enthalpy of just 0.5 ± 0.3 kcal·mol(-1), a value significantly less endothermic than those values suggested from gas-phase model studies. Our results are in accord with neutron scattering measurements that suggest methonium produces only a minimal perturbation in the bulk water structure, which highlights the limitations of gas-phase models. More surprisingly, the incremental withdrawal of the methonium surface from water produces a nonmonotonic response in desolvation enthalpy. A partially desolvated state exists, in which a portion of the methonium group remains exposed to solvent. This structure incurs an increased enthalpic penalty of ~3 kcal·mol(-1) compared to other solvation states. We attribute this observation to the pre-encapsulation dewetting of the methonium surface. Together, our results offer a rationale for the wide distribution of methonium in a biological context and suggest limitations to computational estimates of binding affinities based on simple parametrization of solvent-accessible surface area.
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Jason R
authors.initials: JR
authors.lastname: King
authors.forename: Pan
authors.initials: P
authors.lastname: Wu
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Pelzman
authors.forename: David N
authors.initials: DN
authors.lastname: Beratan
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Toone
mesh_terms: D008725:Bis-Trimethylammonium Compounds / Q000737:chemistry*; D001952:Bridged-Ring Compounds / Q000737:chemistry*; D002151:Calorimetry; D002794:Choline / Q000737:chemistry; D000939:Epitopes; D007093:Imidazoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009502:Neutrons; D011485:Protein Binding; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D012542:Scattering, Radiation; D012997:Solvents; D013499:Surface Properties; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D008725:Bis-Trimethylammonium Compounds; D001952:Bridged-Ring Compounds; D002794:Choline; D000939:Epitopes; D007093:Imidazoles; D000644:Quaternary Ammonium Compounds; D012997:Solvents; D014867:Water; C456276:cucurbit(7)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils; C027917:tetramethylammonium