SEMINARIUM INSTYTUTOWE

Dnia: 24.11.2021 roku (środa)
o godzinie 13:00 w trybie online

referat pt.:

Hydration and ion-binding of small biologically relevant molecules – The case of neurotransmitters

wygłosi

Prof. Richard Buchner

Institute of Physical and Theoretical Chemistry, University of Regensburg, Germany

Szczegóły dotyczące udziału w seminarium znajdują się pod abstraktem

Neurotransmitters (NTs) are a class of small, biologically active molecules essential for signal propagation in living organisms as they transmit signals across the synaptic cleft connecting two neurons or joining a muscle cell and a neuron. In this process the excitation potential moving along the presynaptic nerve triggers NT release from storage vesicles at the end of the axon into the synaptic cleft. The NT then diffuses across this gap and, by binding to specific receptors on the postsynaptic neuron, excites or inhibits the electrical signal carrying information further. Obviously, NT action arises from specific interactions with their receptors. However, in the synaptic cleft these molecules interact with water and other dissolved molecules and ions, which affects their binding behavior, metabolism and reuptake [1,2].
In this contribution, we compare the hydration and -where appropriate- counterion binding of three common neurotransmitters, namely acetylcholine (ACh⁺, as chloride salt), γ-aminobutyric acid (GABA), and glutamate (Glu^-, as sodium salt [3]). These three NTs have similar size and shape but either carry a single positive charge (ACh⁺), are zwitterions (GABA) or combine a zwitterionic moiety with an additional negative charge (Glu^-). Aqueous solutions at natural pH up to the saturation limit were studied with broadband dielectric relaxation spectroscopy (DRS), statistical mechanics at the 1D-RISM and 3D-RISM level, and dilute-solution conductivity measurements (AChCl only).
For all three NTs DRS-detected effective total hydration numbers, Z_t (ACh⁺ ~11, GABA ~11, Glu^- ~40 at c→0), decrease with increasing solute concentrations. Whilst for ACh⁺ and GABA this decrease is linear up to the respective solubility limits (~0.6 and ~6.2 M), that for Glu^- (solubility ~1.8 M) is bimodal with a clear break at ~0.25 M. Interestingly, the high-concentration data for Glu^- extrapolate to Z_t(0) ≈ 15 and thus are again comparable to ACh⁺ and GABA. It was possible to split Z_t into contributions of Z_s moderately bound and Z_ib "frozen" water molecules hydrating the solute. Except for Glu^- at c < 0.25 M, where apparently also the second hydration shell is affected, comparison of Z_s and Z_ib with coordination numbers deduced from RISM suggests that both fractions of DRS-detected bound water are mainly interacting with the ester moiety of ACh⁺ or the carboxylate groups of GABA and Glu^-. At low NT concentrations relevant in the synaptic cleft (< 10-3 M) also hydrophobic hydration of -CH₂- and -CH₃ moieties is important. However, the hydration shell is fragile and with increasing concentration or temperature the NTs loose most of their hydration water molecules. This is corroborated by effective solute dipole moments obtained from the relaxation strengths of ACh⁺, GABA and Glu^-.
Regarding counterion binding by the ionic species ACh⁺ and Glu^-, it appears that the formation of [Na⁺Glu^-]⁰ ion pairs is negligible. On the other hand, with a standard-state association constant of K_A^° = 2.5 M^-1 at room temperature, the formation of [ACh⁺Cl^-]⁰ contact ion pairs is weak but not clearly negligible.
1. C. Zhao, S.Y. Noskov. Biochemistry, 2011, 50, 1848-1856.
2. P.A. Postila, T. Róg. Mol. Neurobiol., 2020, 57, 910-925.
3. S. Friesen, M.V. Fedotova, S.E. Kruchinin, R. Buchner. Phys. Chem. Chem. Phys., 2021, 23, 1590-1600.

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