The Sceptical Chymist | Chemiotics: Auditing P-Chem

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Why would an ex-organic chemist, retired MD do that? The P-chem you need for organic chemistry is pretty simple. You can look at most reactions and figure the overall entropy and enthalpy, and we get pretty good at figuring out delta-deltaG and manipulating it to get reactions to go the way we want.

Well, the answer is because nearly all the really interesting questions in cellular biology involve physical chemistry. Look back at the post of 20 March where throwing a growth factor at a cell resulted in a two fold change in phosphorylation in 924 of 6,600 phosphorylatable sites in 2,244 different proteins. We have some 478 enzymes (called kinases) to accomplish this reaction. Why so many? Because most kinases have a limited number of substrates. Studying the phosphorylation reaction itself (e.g. the classic chemistry) tells you very little. What determines which kinase associates with which substrate? That’s exactly where physical chemistry comes in. The association of one protein with another doesn’t involve covalent (or even ionic) bonds. It’s mostly van der Waals and hydrogen bonding, along with solvent effects. Pure P-Chem.

Non(classical chemical) bonding protein association is crucial in the normal life of the cell (and sometimes in its death). Consider the mediator complex. It is required for the molecular machines which transcribe DNA into RNA (the three RNA polymerases) to actually do their work. Depending on the organism, the mediator complex has between 20 and 30 proteins and a mass of 1-2 megaDaltons. Also, RNA polymerase II itself isn’t just one protein, but 12 (in yeast) with a mass of 500 kiloDaltons — again held together by noncovalent interactions.

A personal reason for studying P-Chem is the protein folding problem, where nary a covalent bond is formed. I’d certainly like to get up to speed to read the literature and find out if the ‘potential energy funnel’ is more than a fancy way to say that (biologic) proteins fold into their final shape quickly. As docs, we do this all the time. Consider the diagnosis of idiopathic thrombocytopenic purpura. Impressive, n’est-ce pas? However, all it means is that you are bleeding because you don’t have enough platelets (a type of blood component) and we don’t know why.

We’ve already been through the 3 laws of thermodynamics, the second introduced by Carnot’s brilliant analysis of the changes in state of an ideal gas as it went around his cycle, and his discovery (better construction) of the concept of entropy. Even after nearly 200 years, the power of his thought is impressive. I doubt that most of you have the time, but you will be similarly impressed with the stunning power of Darwin’s mind if you read “The Origin of Species”. All of you have more background (just by inhaling the zeitgeist) than he did. If you really have a lot of time, read “Darwin’s Ghost” by Steve Jones along with Darwin. Jones updates "The Origin .. " to 2000 chapter by chapter. Although Jones is an excellent writer, Darwin wins each chapter hands down.

Finally, the course is being given at the local state university. It’s very gratifying to see that state universities continue to function as the giant engines of social mobility that they were for my parents’ generation, educating immigrants and the children of immigrants. The present crop of students isn’t predominantly from eastern and southern Europe as my father’s class was at Rutgers 80 years ago. But immigrants they are, and 3 of the students I’ve spoken to were born in Nigeria, Haiti and Poland.

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