Title

Modeling H-Bonded Uncharged (arginine-tyrosine), or "BU(RY)", dyads in activated states of G-protein coupled receptors

Date of Award

8-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Mark S. Braiman

Keywords

arginine, G protein coupled receptors

Subject Categories

Chemistry

Abstract

We have newly synthesized a number of compounds that permit modeling of interactions between tyrosine and arginine side chains. These include alkylguanidine free bases, both alone and complexed and/or covalently bonded to phenol groups. Examples of the newly-synthesized compounds include p-phenol-dodecyl-guanidine free base, p-phenol-ethyl-guanidine free base and the 1:1 mixture of p-cresol and dodecyl guanidine free base. The synthesis of such molecules, which lack other H-bonding groups besides the phenol and guanidine, facilitates isolation of their interaction. UV and IR spectra indicate that neutral phenol and guanidine free base form an unusually strong H-bonding pair, in both crystalline state and in non-polar solvents such as DMSO and hexane. Using UV spectra and the van 't Hoff equation, an experimental value of H = -74  4 kJ mol-1 was obtained for formation of the p-cresol:dodecylguanidine complex in hexane. This was confirmed by computational modeling in vacuo, using density functional theory. The unusual strength of the guanidine-phenol H-bond is also supported by the presence of large continuum absorbance band in IR spectra of the aforementioned compounds; by their high melting points ; and by the short H-bond length between the phenolic oxygen and one (or two) of the guanidine nitrogens as measured in x-ray crystal structures, and in computational models. All these properties associated with strong H-bonding are much weaker or absent, when these compounds are protonated by an external acid, e.g. HBr, to form phenol + guanidinium dyads. The guanidine-phenol H-bond is strong and highly polarizable due to the similar pKa values of proton donor and acceptor. The position of the proton within the H-bond therefore shifts easily in different environments. For example, IR, UV, and 1H NMR spectra showed evidence of increasing proton transfer from phenol to guanidine as the solvent polarity increases from hexane to dimethylsulfoxide. Furthermore, in crystals where methanol co-crystallizes around the H-bonded grouping, IR, 15N solid-state NMR, and x-ray crystallographic measurements showed clearly that there is a near complete proton transfer from phenol to guanidine. We use these results to model h-Bonded Uncharged aRginine-tYrosine dyads, which we term "BU(RY) motifs", and hypothesize that such motifs play a role in activated states of 7-TM proteins including both GPCRs and microbial rhodopsins.

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