Professor J.P. Simons

Physical & Theoretical Chemistry Laboratory

Email Address: john.simons@chem.ox.ac.uk

Telephone: 44 (0) 1865 275 973

Research Group Web Site

Molecular conformation plays a crucial role in the selectivity and function of biologically active molecules. Molecular shape and the interactive forces between the molecule and its nearest neighbours, also control molecular recognition processes. These are involved in virtually all aspects of biological function, ranging from neurotransmission and specific drug-receptor interactions, to enzyme catalysis. Enzyme function, in its turn, is dependent upon specific interactions between neighbouring molecules, bound together at the active site of the enzyme and between the active site and the reactive substrate. It can also be dependent upon the formation of chemically reactive intermediates (transition states) and with charge migration within the enzyme-substrate complex.

The factors which control the conformational landscape involve a subtle balance between 'through bond' and 'through space' interactions within the molecule, and their modification by 'non-bonded' interactions with the environment. Hydrogen-bonded interactions are ubiquitous, operating both within the molecules and externally, especially with neighbouring water molecules. Together, these interactions determine the molecular architecture, the electronic charge distributions and the network of pathways for electron and proton transfer within the molecular structure. Their relative influence and the way in which their co-operative behaviour may control conformational and supra-molecular structure and the specificity of molecular function remain very unclear.

In the last few years, we have developed and exploited very powerful strategies for exploring and mapping the conformational landscapes of small biomolecules, e.g., neurotransmitters and b-blockers; amino-acids, amides and peptides; sugars and oligo-saccharides; and the supra-molecular structures of their size-selected hydrates and molecular complexes. Our approach exploits:

(1) The non-invasive, very low temperature environment of a pulsed nozzle, helium jet gas expansion. This provides an ideal 'laboratory' for resolving individual conformers, preparing size-selected supra-molecular clusters in a controlled way, and facilitating the spectral resolution of complex molecular structures.

(2) The selectivity, resolution and precision of tunable i.r., u.v., and multiple laser excitation methods, coupled with optical and mass spectrometric detection, which provides the experimental input for identifying individual conformers and clusters and assigning their conformational and supra-molecular structures.

(3) The power of ab initio structural computation, which provides the crucially important theoretical input, through which the experimental data can be analysed and interpreted. In this strategy, theory and experiment enjoy a symbiotic relationship - their interaction is truly a co-operative one. Theory provides the “la carte menu” of structural possibilities and the experiments tell us which ones are actually chosen.

(4) The correlation of gas phase structural data with electronic and vibrational CD spectra (e.g., of chiral neurotransmitters) recorded in solution to explore the way in which hydrogen-bonded and non-bonded interactions determine the molecular and electronic structures of both isolated and solvated biomolecular assemblies.

Selected recent publications

1. Getting into shape: conformational and supramolecular landscapes in small biomolecules and their hydrated clusters, E.G.Robertson and J.P.Simons, Phys.Chem.Chem.Phys., 2001, 3, 1-18.
2. Conformational preferences of neurotransmitters: ephedrine and its diastereoisomer, pseudo-ephedrine, P.Butz, R.T.Kroemer, N.A.Macleod and J.P.Simons, J.Phys.Chem.A, 2001, 105, 544-551.
3. A spectroscopic and computational exploration of tryptophan–water cluster structures, L.C. Snoek, R.T. Kroemer, and J.P. Simons, Phys.Chem.Chem.Phys., 2002, 4, 2130-2139.
4. Neurotransmitters in the gas phase: infrared spectroscopy and structure of protonated ethanolamine, N.A.Macleod and J.P.Simons, Phys.Chem.Chem.Phys., 2004, 6, 2821-2826.
5. Sugars in the gas phase: spectroscopy, conformation, hydration, co-operativity and selectivity, J.P.Simons, P.Çarçabal, B.G.Davis, D.P.Gamblin, I.Hünig, R.A.Jockusch, R.T.Kroemer, E.M.Marzluff and L.C.Snoek, Intl. Revs. Phys. Chem., 2005, 24, 489 - 532.
6. Building-up key segments of N-glycans in the gas phase: intrinsic structural preferences of the alpha(1,3) and alpha(1,6) dimannosides, P. Çarçabal, I. Hünig, D. P. Gamblin, B. Liu, R. A. Jockusch, R. T. Kroemer, L. C. Snoek, A. J. Fairbanks, B. G. Davis, J. P. Simons, J. Amer. Chem. Soc., 2006, 128, 1976-1981.