Structures of Biomolecules
in the gas phase
-JPSGroup-
Neurotransmitters and
b-blockers
Introduction
Understanding the structure
and interactions of elementary biomolecular building blocks is fundamentally
important in elucidating the mechanisms of biological processes, and in
designing the artificial drugs that mimic, activate or suppress the function
of bio-active systems. The importance of making the links between computated
and experimentally obtained molecular structures in the gas phase, in the
condensed phase and in the 'organised bio-phase' is well illustrated by
a recent computated structure of (protonated) adrenaline, bound at a trans-membrane
(TM7) protein site, see Fig. 1.
The protein structure is based upon X-ray data, the structure of the neurotransmitter
is based upon an assumed force field. Experimental data suggest
that the most likely orientation of the 'tail' is perpendicular to the
aromatic ring, and also that the two hydroxyl groups in the catechol are
much more likely to be H-bond donors (to the neigbouring residues) than
acceptors. In short, this emphasises the importance of obtaining experimental
data on these systems, in order to achieve a correct view of the real
structure, which is of additional importance for drugs design.
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Figure 1. The TM7 adrenergic
receptor with an adrenaline molecule bound inside (calculated minimum energy
structure, D. Donnelly, J.B.C. Finlay and T.L. Blundell, http://www.gpcr.org/7tm/models).
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In the JPS group, the
structural landscapes of several ephedrine- and adrenaline-related neurotransmitters
and their hydrated clusters have been studied in the gas phase (see Fig.
2 and references below).
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Figure 2. Structures of
some TM7 neurotransmitters: the beta-blocker propanolol, with the investigated
beta-blocker models 2-phenoxyethanol (POX) and 3-amino-1-phenoxy-2-propanol
(AMPOX). Underneath are shown adrenaline and the ephedra molecules ephedrine
and pseudoephedrine.
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The latest results
concern assignments of the monomeric and hydrated structures of the diastereoisomers
pseudoephedrine and ephedrine. These two ephedra molecules differ only
in their chiral centres, but this results in very different physiological
and chemical behaviour (see Fig. 3)!
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Figure 3. Ephedrine and
pseudoephedrine results: monomer R2PI spectra and assignments.
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The 3-D conformational landscapes of ephedrine
and pseudoephedrine have been determined using all spectroscopic tools
available to us (see Fig. 4): electronic spectroscopy
(R2PI and LIF), rotational band contours with simulated bandcontours from
ab
initio calculations, and infrared ion dip spectroscopy.
(a) |
(b) |
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Figure 4. (a) Assignment
of Ephedrine-water1: LIF spectra, rotational bandcontours, infrared spectra
and predicted structures.
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(b) Assigned structures
of pseudoephedrine-W1 and -W2.
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Our current projects
At the moment we are working on a project to
assign the main conformer origin bands in noradrenaline, using UV-holeburn
and IR-UV ion dip spectroscopy, combined with the predictions from ab
initio calculations (see Fig. 3).
(a)
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(b)
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Figure 3. (a)
Nor-adrenaline ab initio structures (MP2/aug-cc-pVDZ(sp)//B3LYP/6-31+G*,
by T. van Mourik).
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(b) Noradrenaline R2PI
spectrum (top), with UV holeburn spectra on bands G and D respectively,
confirming their assignment as separate conformer origins.
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We are also investigating some of the systems
that have previously been studied in the gas phase, like the ephedra molecules,
in the solution phase, see the link to Circular
Dichroism spectroscopy.
A new topic of interest concerns the protonated
structure of neurotransmitters, see therefore the link to Protonated
species.
References
Molecular conformation in the
gas phase and in solution, P. Butz, G.E. Tranter and J.P. Simons, Phys.
Chem. Comm., 2002, 5 (14), 91–93.
Conformation, structure and
molecular solvation: a spectroscopic and computational study of 2-phenoxyethanol
and its singly and multiply hydrated clusters, N.A. Macleod and J.P.
Simons, Chem. Phys., 2002, 283, 221.
Protonated neurotransmitters
in the gas phase: clusters of ethanolamine with phenol,
N.A. Macleod and J.P. Simons, 2002, in preparation.
Hydration of a noradrenaline
analogue: a computational and spectroscopic study of 2-amino-1-phenylethanol
(APE), N.A. Macleod and J.P. Simons, 2002, in preparation.
Hydration of a model beta-blocker:
2-phenoxyethylamine, N.A. Macleod and J.P. Simons, 2002, in preparation.
Hydration of neurotransmitters:
a spectroscopic and computational study of ephedrine and its diastereoisomer
pseudoephedrine, P. Butz, R.T. Kroemer, N.A. Macleod, and J.P. Simons,
Phys.
Chem. Chem. Phys., 2002, 4, 3566-3574.
Conformational preferences
of neurotransmitters: Ephedrine and its diastereoisomer, pseudoephedrine,
P. Butz, R.T. Kroemer, N.A. Macleod and J.P. Simons, J. Phys. Chem.
A, 2001, 105, 544-551.
Conformational preferences
of neurotransmitters: norephedrine and the adrenaline analogue, 2-methylamino
1-phenyl ethanol, P. Butz, R.T. Kroemer, N.A. Macleod, E.G. Robertson
and J.P. Simons, J. Phys. Chem. A, 2001, 105, 1050-1056.
Infrared ion-dip spectroscopy
of a noradrenaline analogue: hydrogen bonding in 2-amino-1-phenylethanol
and its singly hydrated complex, R.G. Graham, R.T. Kroemer, M. Mons,
E.G. Robertson, L.C. Snoek and J.P. Simons, J. Phys. Chem. A, 1999,
103,
9706-9711.
Conformations of 2-phenyl ethanol
and its singly hydrated complexes: UV-UV and IR-UV ion-dip spectroscopy,
M. Mons, E.G. Robertson, L.C. Snoek and J.P. Simons, Chem. Phys. Letters,
1999,
310, 423-432.
Conformational landscapes in
flexible organic molecules: 4-hydroxy phenyl ethanol (p-tyrosol) and its
singly hydrated complex, M.R. Hockridge, S.M. Knight, E.G. Robertson,
J.P. Simons, J. McCombie and M. Walker, Phys. Chem. Chem. Phys.,
1999, 1, 407-413.
Neurotransmitters
| Sugars | Amino
acids, peptides | Protonated
species | Circular Dichroism
spectroscopy
Last updated 08/10/2002
by
Lavina Snoek