The Sceptical Chymist | Chemiotics: Binding physicality rather than chemicality

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Organic chemists love mechanism, subtlety and specificity. Books have been written about pushing arrows. Medicinal chemists are always worrying about making molecules which they can dock into either the active site or an allosteric site of a target protein. The fit must be quite close, and a recent post over at In the Pipeline notes that ‘You’ll have whole series of compounds that have to have a methyl group at some position, or they’re all dead. Nothing smaller, nothing larger, nothing with a different electronic flavor: it’s methyl or death.’

So making an organic molecule that responds to the physical properties of its surroundings – rather than the bonding structure of the molecules surrounding it – stands this sort of work on its head. As usual, nature got there first. Here are two examples.

Cells need to respond to the amount of cholesterol they contain, and make more if lacking. Cholesterol is poorly soluble in water, being found mostly in membranes. Here cholesterol functions as a fluidizer, making the long hydrocarbon chains of phospholipids and other lipids more disordered in order to fit around it. So cholesterol doesn’t exist just to make pharmaceutical companies rich. A similar mechanism probably explains why unsaturated fatty acids (such as oleic acid) found in membranes have cis rather than trans double bonds (and in the middle of the chain to boot), making them harder to pack.

So if your membranes have less cholesterol they become stiffer. This stiffness is sensed in some way by several membrane embedded proteins (SCAP, INSIG1). SCAP then moves SREBP, another membrane embedded protein (along with its associated membranes) to another site in the cell where it is cleaved. It took years to figure out how water got inside the hydrophobic environment of the membrane to cleave (hydrolyze a peptide bond) SREBP. One of the SREBP cleavage products is then able to leave the membrane, migrate to the nucleus, bind to DNA and turn on genes in the cholesterol synthesis pathway. Elegant no?

A second example. The DNA in our cells is under constant chemical attack. Ultraviolet light produces cyclobutane dimers of adjacent pyrimidine nucleotides. Nucleotides fall off the backbone or have attached molecular fragments which alter their stereochemistry. Then there are the mismatches (an A or a T pairing with G rather C etc., etc.). Somehow, proteins scan DNA for these lesions (and find them). One such protein complex is DDB1/DDB2 (see here and here) which recognizes a very broad range of DNA lesions which are subsequently targeted for repair. DDB1/DDB2 binds to pyrimidine dimers (which distort the helix) and to DNA with crosslinked bases (e.g., due to cisplatin, psoralen), and also to DNA lacking nucleotide bases (just the opposite of crosslinked DNA).

How can one protein complex do all this? One theory has it that DNA lesions are recognized by their increased flexibility (because of decreased stability of base pairing and stacking in damaged DNA). This enables DNA lesion finding protein complexes such as DDB1/DDB2 to target a broad range of DNA pathologies for repair (without recognizing them specifically). They are binding to the effect of chemistry, rather than the chemistry itself, e.g., they are binding to a physical property of damaged DNA rather than its chemical structure.

Only the chemist can fully appreciate the wonder of what’s going on under the cellular hood. In this we are fortunate, even if regarded as somewhat grubby by everyone else. Pascal’s thinking reed and all that.

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