Anslyn pp. 201 – 258

p. 207 — Molecular recognition — exactly what physical organic chemistry must address if it is to be more than chemical navel-gazing (fascinating though this is to me).  The fact that 7 transmembrane G protein coupled receptors (GPCRs) can distinguish between dopamine and norepinephrine, which differ by a single oxygen atom binding both in the center of the ring of 7 alpha helices, along with the other examples given in the first paragraph shows its importance to molecular biology, biology, medicine and life.  Hopefully physical organic chemistry has something useful to say about this.  

I learned a fair amount I didn’t know about proteins in the previous chapter, even though it concerned itself with solvents and solutes.  Looking forward.

p. 208 — Important to note that the term ‘binding constant’ refers either  to Ka or Kd — not just Ka.  This wasn’t made clear in the text.  The first example is on p. 209 where the term binding constant is used for the association constant. 

p. 208 — Host and guest discussion.  In most examples of biologic and medical interest the host is a protein.  This means that for a polypeptide with an molecular mass of at least 1000 Daltons (only 10 amino acids), a 1 MOLAR solution is physically impossible — you can’t get a mole of the stuff into a liter.  Drop this by at least 2 orders of magnitude, which means that you can’t even get 10 milliMoles of most proteins into a liter.  So the discussions of biologic interest will have [H] and (of necessity) [HG] rather low (usually microMolar or less).  

p. 210 — The discussion of why [ H ] and [ G ] increase more than [ HG ] with dilution is quite good.  Entropy conquers all ! ! ! 

      Also good point about Ka (and pKa) for acids — it’s really a dissociation constant. The nomenclature however is entrenched.

p. 213 — I realize this isn’t physics book, but an explanation of where ln(Tf/Ti) comes from (the integral of 1/T) would be good.  Otherwise it’s just magic. 

p. 215 — In the next edition you might mention a few allosteric effects which will grab the readers attention — such as those of the benzodiazepine class of drugs (librium, valium, xanax, ativan, halcion etc. etc.) which bind to a receptor for the major inhibitory neurotransmitter in the brain (gamma amino butyric acid) in an allosteric fashion, altering its conformation and making it easier for it to bind gamma amino butyric acid.  This is better than “This is commonly found in Nature”.  Interestingly, the barbiturate anticonvulsants (phenobarbital is one) act the same way.

p. 216 — The enthalpy entropy compensation is one of those types of reasoning that chemists are good at (it is obvious once you think of it), but very difficult to put into mathematical form. 

p. 217 — The derivation of 4.24 from 4.2 and [H]o = { HG ] + [H] would be good. 

p. 217 — 222 –Binding isotherms.   This sort of stuff has always left me cold.  It takes a lot work for the hapless graduate student doing it, and there is always some other explanation for the data, which puts the wretch back in tha lab for another 6 months of experiments.  This is particularly true of kinetic work (which is similar but not covered in this section).  I saw Westheimer pull this on a number of people from ’60 – ’62.  Unlike a lot of the clever experiments in the book, (see “Proton Sponges” on p. 179), this sort of work rarely proves anything.

p. 223 — It is crucial when equating deltaH to the heat absorbed, that the system do no work.  In experiments done under atmospheric pressure, this means no PV work as neither P nor V change (usually).  However there are other types of work which as system can do (electrical for one) and these must be excluded as well. 

p. 224 — The crown ether story is fascinating.  Nothing about it in Clayden so it’s new to me.  I do remember some mumbling about it when people were trying to explain why there was so little sodium and so much potassium in cells.  See the comments on activity coefficients p. 156.

Something rather similar occurs in ion channels letting potassium ions through while making it at least 10 times more difficult for the smaller sodium ion to get through.  There is tight coordination of the potassium ion by the carbonyl oxygens (italics) of the protein backbone, meaning that stripping K+ of its waters is energetically neutral.  The smaller sodium ion doesn’t fit as tightly here so there is the energetic cost of a poorly coordinated positive charge with no waters around in the middle of the membrane (with its low dielectric constant).  The coordination of K+ by carbonyls came as a huge shock to those studying ion channels when the first crystal structures became available.   The crown ethers came much earlier (1967) than crystal structures of membrane proteins, but I wonder if the neurophysiologists and crystallographers knew of them — probably they did as it was a great example of differential coordination of ions slightly different in size.  

pp.  225 – 248 — A bunch of fascinating chemistry, most of which was unfamiliar.  Not much to say about it except about cation pi bonds.  

 p. 240.  Rather interesting that Wikipedia calls cation pi bonds, the Dougherty effect, but that Dougherty is too modest to say so in the text.    [ Nature vol. 458 pp. 384, 534 – 537 ’09 ] If nicotine bound as tightly to to the muscle nicotinic receptors as it does to brain receptors, cigarette smoking would cause fatal muscle contractions.  Acetylcholine (AcCh) makes a cation pi interaction when it binds to the brain AcCh receptor (AcChR).  Nicotine (despite its positive charge at physiologic pH — perhaps because the positive charge is fixed in AcCh and reversible in nicotine, or perhaps the water must be stripped) doesn’t make a similar bond with the muscle AcChR.  A single amino acid difference between the brain receptor responsible for nicotine addition (alpha4beta2) and muscle receptors explains the binding difference.  

p. 249 — The biotin streptavidin complex is widely used in biologic research to tag molecules and follow them throughout the cell.  This is due to the very high Ka of 10^15.

p. 251 — Cyclobutadiane at last.  Sacre Bleu ! ! 
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  • MJ  On July 6, 2011 at 8:58 am

    Hope you don’t mind….

    Re: p. 208 – Completely agreed. I strive to never let the phrase “binding constant” escape my lips any longer, as it’s inherently unclear, especially to interdisciplinary audiences. I especially dislike it when people get sloppy about this in a paper, especially if they don’t make it immediately clear how they mean it. Or if they refer you back to an earlier paper for their particular theoretical model – you really should explain yourself on this point in every paper, even if it’s just in the text of the figure or somewhere.

    Re: p. 213 – Wouldn’t it just be that as the integral of (1/T) is ln T (“plus a constant!” my one calc professor would always remind us), and if you’re evaluating T at two points (presuming the subscripts mean T[initial] and T[final] here), then you have ln (T[final]) – ln (T[initial])? Which given that one of the properties of logarithms is that ln (a) – ln (b) = ln (a/b), you’d end up with ln (T[final])/(T[initial]).

    Re: p. 217 to 222 (binding isotherms) – Very much inclined to agree. I’ve never been utterly convinced of an argument solely on such data, and as always seems to be the case in my experience, no one ever seems to do theirs in such a manner so that it can further validate (or not!) the comparable data others publish. I do think these types of studies have a place, but it is usually in the preliminary characterization stage of a project and – for better and worse – in cases where there isn’t much else to go on, in terms of functional assays. If neither binding partner has a measurable activity of some type that changes upon binding, it can be a challenge.

    The discussion of brain vs muscle AcChR’s interactions with nicotine sounds like a great case study to put on my to-read list.

  • michael012  On December 26, 2011 at 5:33 pm

    Question.. why pKa values are used rather than Ka-values when dissociation constants are mentioned like what this website says ( )?

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