For many years chemists have theorized that the peculiarities of enzyme active sites and biological receptors can be ascribed to the fact that they provide reaction media that differ greatly from bulk solvent. One hypothesis, originally put forth about 35 years ago, holds that the gas phase represents the closest analogy to the milieux of binding sites in proteins. Our research group is one of the few in the world that is seeking to replace speculation with fact by pursuing concurrent studies of organic reactions in the gas phase and in biological receptors. In this work we make use of (and, in some cases, have invented) new techniques in mass spectrometry, as well as novel methods for tagging and purifying receptors.

Biological Receptor Sites

Our focus has been on the binding and recognition of small (m.w. <250), electrically uncharged molecules. We have been especially interested in receptors for the sense of smell in vertebrate species. Since very little is known about these receptors, new chemistry has been devised for in vivo study.

We can make educated guesses about mechanisms for molecular recognition and binding specificity. For receptors that identify small, nonpolar molecules, molecular shape does not offer enough information for a binding site to distinguish different compounds. Other kinds of information, including chemical reactivity, must play a role. In the sense of smell, we have uncovered evidence that Schiff base formation (shown above), plays a role in olfactory detection of ketone-containing odorants. This chemistry is being explored with a number of new approaches, including Two-Step Affinity Chromatography and Accelerator Mass Spectrometry.

This chemistry is being explored with a number of new approaches, including Two-Step Affinity Chromatography and Accelerator Mass Spectrometry.

Gas Phase Organic Chemistry

Electrically charged organic molecules enjoy a vastly different environment in the gas phase than in bulk solvent. Solvation is negligible, and counterions are absent. Chemical reactions take place on a timescale that is much faster than the timescale for exchange of energy with the ambient heat bath. Despite these substantial differences, we have found at least one major feature of gas phase ion chemistry that bears a strong resemblance to reactions in solution: a charged and an uncharged molecule experience encounters of long duration, in which a variety of orientations are explored prior to chemical reaction. Therefore, the outcome of an ionic reaction in the gas phase is not determined by the physics of collision so much as by the chemistry of the reactants.

Many techniques are used at UCR to probe the stereo- and regiochemistry of the reactions of organic ions in the gas phase, among them EBFlow (for examining the neutral products of ionic reactions in the gas phase) and the whole range of modern instrumental methods in NMR and Mass Spectrometry. We have found out that SN2 displacements go by backside attack in the gas phase, just as they do in solution. In general, we are discovering aspects of gas phase chemistry that ought to hold true for reactions in biological media as well.

Publications

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