Thursday, September 3, 2015

Order and Disorder: who to marry

In yesterday's lecture I briefly discussed the connection between 2 apparently different types of disordering process: thermal agitation (= temperature) in phase transitions such as melting of ice, boiling of water and loss of magnetism, and mutation in molecular evolution. The main type of mutation is "point mutation", the occurrence of incorrect Crick-Watson base-pairing (i.e. other than A-G or C-T). The latter results from the fact that the difference in the free energy change (in water) that accompanies correct or incorrect pairing ("delta E") is not infinite (in fact it's only around 2 kcal/mole*)  - hydrogen bonding can occur between incorrect pairs (e.g A-A or A-C), though not as snugly as for correct pairing.

The Boltzmann equation states:

Phi/Plo = exp -(deltaE/kT)

where phi/lo are the (mutually exclusive) probabilities of being in hi energy versus lower energy states and kT is the thermal energy (0.6 kcal/mole). Here we can interpret the hi energy state as incorrect pairing. Inserting the above energy values we get error rate = exp- 3.4 ~ 0.03 i.e. around 3%!
As discussed by Kunkel DNA polymerases can achieve an error rate approaching 10^-10 using 3 combined, strategies: active site geometry (e.g. exclusion of water),  proofreading and mismatch repair.

Obviously thermal agitation (i.e. T)  plays a crucial role in mutation. That's why a man's testicles hang down from the body: it's cooler, though more vulnerable and less elegant than the female arrangement. Note that while I argued (in the Notes and the Lecture) that the high human intergeneration mutation rate favored rapid evolution (broadening of the quasi-species), at the individual selection level (mate choice) it always pays to choose the younger man, who has the lowest mutation rate (other things being equal, which they rarely are).

After the lecture a student asked if this idea (the battle between order and disorder) would be the major theme of the course. I replied, somewhat hastily, that once we got into the brain, this would not be a major theme - we will usually assume synapses, neurons and the brain work perfectly. But this was not quite right: we will see that thermal agitation underlies diffusion which powers the brain's batteries, and that non-thermal phenomena can cause disorder, or at least total confusion! More to the point, the conceptual/quantitative approach I introduce in the early part of the course will often crop up again as we become neural (and some of these ideas will have direct applications, e.g. in neural networks).
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*I multiplied energies be molecule  by N, Avogadro's number (6X 10^23, meaning 6 times ten to the power twenty three), converting kT to RT. In other words, one can use either energies per molecule or energies per mole in the Boltzmann formula, but one must be consistent so N cancels on top and bottom)

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