The Beauty of Organic Chemistry Revealed
Browsing through the recent issue of Nature, I stumbled upon an headline that triggered fond memories of freshmen organic chemistry at Yale: “Electrostatic catalysis of a Diels–Alder reaction.” In a remarkably elegant experiment, the authors show that applying a directed electric field can accelerate a chemical reaction.
http://www.nature.com/nature/journal/v531/n7592/full/nature16989.html
Using single molecule experiments, Coote’s Lab at the Australian National University, together with their Spanish collaborators, discovered that applying an electric field to a reaction can contribute to favorable resonance structures of the transition state, lowering the activation energy and accelerating the reaction rate. The finding is remarkable because chemists previously believed that only redox reactions, generally involving electron transfers, can be accelerated by manipulating voltage changes.
The beauty of the result can be seen in its intuitive straightforwardness: all chemical bonds consist of electric forces, hence we should expect application of electric fields to affect how easy it is to break existing an form new chemical bonds. Yet scanning my distant memory of class notes from Orgo, I recall we never thought of electric fields as tools to manipulate reaction rates. Instead, the levers available at our disposal as chemists were temperature, concentration, pH (or acidity of the environment), and availability of catalysts.
Second, the beauty of the Diels-Alder is that it is a canonical mechanism for carbon bond formation and precise addition of functional groups to carbon backbones. Coote’s team used Diels-Alder only as an experimental illustration; their finding is relevant not only to all carbon chemistry but to thermodynamics of any chemical reaction. Reminiscent of other famous one-liners in important scientific articles, Coote’s team writes: “Our results are qualitatively consistent with those predicted by quantum-chemical calculations in a theoretical model of this system, and herald a new approach to chemical catalysis.” Yes, you read that right: “…and herald a new approach to chemical catalysis.” That definitely sends goosebumps down my neck.
To me, this new finding immediately raises the question about the significance of electric fields for catalysis of molecular reactions within human cells, including DNA and RNA chemistry, remodeling of the chromatin and protein synthesis. I started my research in biochemistry with classical studies of ribozyme self-splicing in the Herschlag Lab at Stanford. In my study of ion metals’ role in stabilizing the RNA-splicing transition state, I learned that the reality of life chemistry in the human cell is much more complex that what we can model with single-molecule experiments. Each of our DNA and RNA molecules baths in a sea of metal ions, that exact exquisite dynamic control of the electric field around these biological molecules. We have know for some time that this sea of metal ions forms local areas of differential positive charge density to orchestrate the three-dimensional structure of the folded nucleic acid molecule. We have also known that in the case of the ribozyme, metal ions play a key role in stabilizing the transition state of the folded RNA strand, allowing for cleaving and re-arrangement of carbon bonds leading to self-splicing.
If directed electric fields can catalyze chemical reactions, is it possible that the human cell regulates its own local electric fields to carry out the chemistry of life?
This may not be so unreasonable to believe. Consider that we already know that electric gradients play a key role in cell biology. Perhaps the two best known examples are cellular respiration and neuronal signaling. In the case of the former, the electron chain on the mitochondrial membrane utilizes downward voltage gradient for generation of energy that powers all life processes. In the case of the latter, neurons use electric action potential to send information along its axons and regulate the release of neurotransmitters as signals to neighbors in the neural network.
Understanding that organizing the direction and the position of electric fields can drive carbon bond formation enables us to ask whether a living cell can use electric fields to regulate its own reactions. To me, this question is especially interesting when we look at the reactions within the cell’s nucleus. One of the greatest unsolved puzzles of modern biology is how human cells architect the structure housing our organism’s genetic code, orchestrating with perfect precision position and accessibility of specific genes to the complex nuclear machinery of transcription. All of human life is ultimately reduced to what genes get expressed, how much, when and where; while our genome holds the information on who we can become, the regulation of expression determines who we are — from a single cell to the whole organism.
Currently, biologists look at chemical properties of molecular machines working inside the nucleus, and only recently at physical properties of dynamic scaffolding and molecular motors moving things within and across the nuclear envelope. A far-reaching question that arises from the chemists’ finding above is whether the human cell can generate, maintain and manipulate directed electric fields that are temporarily and spatially specific enough to direct its intracellular reactions. In other words, could directed electric fields such as those illustrated in the Diels-Alder reaction play a role in modification and opening of the chromatin, binding of the transcription factors, and synthesis and processing of RNA?
Single-molecule experiments, combined with existing nanotechnology tools should already allow biologists to start answering these questions. In engineering applications, electric fields are already used (albeit in a very different way) as the basis of a new, in vitro DNA sequencing technology. This shows promise that high precision experimental tools will enable higher resolution picture of the mysterious processes at the core of human genetic expression — and life itself.
