Posted on behalf of Retread
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.
Studying P-Chem is a worthy endeavor indeed and I am trying to do it myself. I did study P-Chem before, but one of the reasons I need it more now is the same as yours- to understand the protein folding problem. I might actually end up doing some work in on it later and P-Chem would be indispensable.
Which books are your favorite? I like Alberty & Silbey and the terrific book by Ken Dill called “Molecular Driving Forces”. I would strongly suggest the Dill book to you; it’s hands down the best book detailing the application of statistical thermodynamics, electrostatics and other topics to biochemistry that I have encountered. It contains an awesome amount of information, one of the best treatments of entropy that I have encountered and the clearest derivation of the Poisson-Boltzmann electrostatic approach to studying ionic biological solutions. I suddenly understood electrostatic fields in proteins better than before. It’s not exactly easy going but every minute is worth the challenge.
Wavefunction: One of the joys of retirement, is that you don’t have to do things quickly, so I’m just sitting in P-chem class 3 hours a week listening and thinking about the material — with no distractions (such as the internet). By the end of the class in a few months I should be through the Hubbards’ marvellous book “Vector Calculus, Linear Algebra, and Differential forms” (3rd Edition), so that I’ll actually understand the mathematics underlying P-Chem, rather than muttering various formulas as incantations without understanding them, as I’ve done in the past. I’ll tackle the more advanced tomes at that point.
Thanks for the reference to Dill, I’ve heard good things about it.
On a historical note (what else are old guys good for?), back in grad school I audited a statistical mechanics course given by E. Bright Wilson (of Pauling and Wilson) mostly just to hear him lecture. He used no notes, and each lecture was started back at the beginning deriving everything (quickly) up to where he’d left off previously and then moving on. An incredible performance — would that any of us understand our field as well. Unfortunately I’ve lost the notes I took.
Finally, do you think the ergodic hypothesis applies to protein folding, given the Levinthal Paradox (see the 23 April post — Why should a protein have one shape?).
As I continue to audit P-Chem, Ernst Mach is looking better and better. Recall that he was Boltzmann’s adversary, decrying the existence of atoms as an unnecessary explanatory device (see the 16 July post — Unrequired Reading). With 20/20 hindsight, Mach’s position appears perverse. However, watching the Gibbs free energy, the van’t Hoff law, the Clausius-Clapeyron equation and Henry’s law appear from measurements and reasoning about enthalpy and entropy, I’m amazed at just how much can be done using measurement and 1/T plots alone. Atoms are nowhere to be found. That’s not to say that atomic explanations aren’t frequent asides during the lectures, but they are like icing on the cake rather than the cake itself.
I’m also extremely curious about the applicability of the ergodic hypothesis, and therefore the validity of a statistical mechanical treatment, to the protein folding problem. The axiom that the time average is equal to the ensemble average seems a bit extreme considering proteins cannot possibly sample all of conformation space (as Retread said, a la Levinthal’s Paradox).